N-substituted piperidine derivatives as serotonin receptor agents

ABSTRACT

Disclosed herein are compounds of Formula I,  
                 
or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof. Also disclosed are methods of inhibiting an activity of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more of the compounds of Formula I. Disclosed are also methods of inhibiting an activation of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more of the compounds of Formula I. Furthermore, methods of treating psychotic disease using a compound of Formula I are disclosed.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.11/299,566, filed Dec. 12, 2005, by Andersson et al., and entitled“N-SUBSTITUTED PIPERIDINE DERIVATIVES AS SEROTONIN RECEPTOR AGENTS,”which claims priority to U.S. application Ser. No. 10/601,070, filedJun. 20, 2003, by Andersson et al., and entitled “N-SUBSTITUTEDPIPERIDINE DERIVATIVES AS SEROTONIN RECEPTOR AGENTS,” which in turnclaims priority to U.S. Provisional Application Ser. No. 60/391,269,filed Jun. 24, 2002, by Andersson, and entitled“N-(HETEROCYCLYLALKYL)PIPERIDINE DERIVATIVES AS SEROTONIN RECEPTORAGENTS,” all of which are hereby incorporated by reference herein intheir entirety, including any drawings.

FIELD OF THE INVENTION

The present invention relates to azacyclic compounds withpharmacokinetic properties for the treatment of symptoms, diseases anddisorders associated with monoamine receptors, including serotoninreceptors.

BACKGROUND OF THE INVENTION

Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in thefunctioning of the mammalian body. In the central nervous system, 5-HTis an important neurotransmitter and neuromodulator that is implicatedin such diverse behaviors and responses as sleeping, eating, locomotion,perceiving pain, learning and memory, sexual behavior, and controllingbody temperature and blood pressure. In the spinal column, serotoninplays an important role in the control systems of the afferentperipheral nociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)).Peripheral functions in the cardiovascular, hematological, andgastrointestinal systems have also been ascribed to 5-HT. 5-HT has beenfound to mediate a variety of contractile, secretory, andelectrophysiologic effects including vascular and nonvascular smoothmuscle contraction, and platelet aggregation. (Fuller, Biology ofSerotonergic Transmission, 1982; Boullin, Serotonin In MentalAbnormalities 1:316 (1978); Barchas, et al., Serotonin and Behavior,(1973)). The 5-HT2A receptor subtype (also referred to as subclass) iswidely yet discretely expressed in the human brain, including manycortical, limbic, and forebrain regions postulated to be involved in themodulation of higher cognitive and affective functions. This receptorsubtype is also expressed on mature platelets where it mediates, inpart, platelet aggregation, one of the initial steps in the process ofvascular thrombosis.

Given the broad distribution of serotonin within the body, it isunderstandable that tremendous interest in drugs that affectserotonergic systems exists (Gershon, et al., The Peripheral Actions of5-Hydroxytryptamine, 246 (1989); Saxena, et al., J. CardiovascularPharmacol. 15: Supp. 7 (1990)). Serotonin receptors are members of alarge human gene family of membrane-spanning proteins that function astransducers of intercellular communication. They exist on the surface ofvarious cell types, including neurons and platelets, where, upon theiractivation by either their endogenous ligand serotonin or exogenouslyadministered drugs, they change their conformational structure andsubsequently interact with downstream mediators of cellular signaling.Many of these receptors, including the 5-HT2A subclass, are G-proteincoupled receptors (GPCRs) that signal by activating guanine nucleotidebinding proteins (G-proteins), resulting in the generation, orinhibition of, second messenger molecules such as cyclic AMP, inositolphosphates, and diacylglycerol. These second messengers then modulatethe function of a variety of intracellular enzymes, including kinasesand ion channels, which ultimately affect cellular excitability andfunction.

At least 15 genetically distinct 5-HT receptor subtypes have beenidentified and assigned to one of seven families (5-HT1-7). Each subtypedisplays a unique distribution, preference for various ligands, andfunctional correlate(s).

Serotonin may be an important component in various types of pathologicalconditions such as certain psychiatric disorders (depression,aggressiveness, panic attacks, obsessive compulsive disorders,psychosis, schizophrenia, suicidal tendency), certain neurodegenerativedisorders (Alzheimer-type dementia, Parkinsonism, Huntington's chorea),anorexia, bulimia, disorders associated with alcoholism, cerebralvascular accidents, and migraine (Meltzer, Neuropsychopharmacology,21:106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152(1999); Glennon, Neurosci. Biobehavioral Rev., 14:35 (1990)). Recentevidence strongly implicates the 5-HT2 receptor subtype in the etiologyof such medical conditions as hypertension, thrombosis, migraine,vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia,sleep disorders and appetite disorders.

Schizophrenia is a particularly devastating neuropsychiatric disorderthat affects approximately 1% of the human population. It has beenestimated that the total financial cost for the diagnosis, treatment,and lost societal productivity of individuals affected by this diseaseexceeds 2% of the gross national product (GNP) of the United States.Current treatment primarily involves pharmacotherapy with a class ofdrugs known as antipsychotics. Antipsychotics are effective inameliorating positive symptoms (e.g., hallucinations and delusions), yetthey frequently do not improve negative symptoms (e.g., social andemotional withdrawal, apathy, and poverty of speech).

Currently, nine major classes of antipsychotics are prescribed to treatpsychotic symptoms. Use of these compounds is limited, however, by theirside effect profiles. Nearly all of the “typical” or older generationcompounds have significant adverse effects on human motor function.These “extrapyramidal” side effects, so termed due to their effects onmodulatory human motor systems, can be both acute (e.g., dystonicreactions, a potentially life threatening but rare neuroleptic malignantsyndrome) and chronic (e.g., akathisias, tremors, and tardivedyskinesia). Drug development efforts have, therefore, focused on newer“atypical” agents free of these adverse effects.

Antipsychotic drugs have been shown to interact with a large number ofcentral monoaminergic neurotransmitter receptors, includingdopaminergic, serotonergic, adrenergic, muscarinic, and histaminergicreceptors. It is likely that the therapeutic and adverse effects ofthese drugs are mediated by distinct receptor subtypes. The high degreeof genetic and pharmacological homology between these receptor subtypeshas hampered the development of subtype-selective compounds, as well asthe determination of the normal physiologic or pathophysiologic role ofany particular receptor subtype. Thus there is a need to develop drugsthat are selective for individual receptor classes and subclassesamongst monoaminergic neurotransmitter receptors.

The prevailing theory for the mechanism of action of antipsychotic drugsinvolves antagonism of dopamine D2 receptors. Unfortunately, it islikely that antagonism of dopamine D2 receptors also mediates theextrapyramidal side effects. Antagonism of 5-HT2A is an alternatemolecular mechanism for drugs with antipsychotic efficacy, possiblythrough antagonism of heightened or exaggerated signal transductionthrough serotonergic systems. 5-HT2A antagonists are therefore goodcandidates for treating psychosis without extrapyramidal side effects.

Traditionally, these receptors have been assumed to exist in a quiescentstate unless activated by the binding of an agonist (a drug thatactivates a receptor). It is now appreciated that many, if not most, ofthe GPCR monoamine receptors, including serotonin receptors, can existin a partially activated state in the absence of their endogenousagonists. This increased basal activity (constitutive activity) can beinhibited by compounds called inverse agonists. Both agonists andinverse agonists possess intrinsic activity at a receptor, in that theyalone can activate or inactivate these molecules, respectively. Incontrast, classic or neutral antagonists compete against agonists andinverse agonists for access to the receptor, but do not possess theintrinsic ability to inhibit elevated basal or constitutive receptorresponses.

The present investigators have recently elucidated an important aspectof 5-HT2A receptor function by applying the Receptor Selection andAmplification Technology (U.S. Pat. No. 5,707,798, 1998; Chem Abstr.128:111548 (1998) and citations therein), to the study of the 5-HT2subclass of serotonin receptors. R-SAT is a phenotypic assay of receptorfunction that involves the heterologous expression of receptors inmammalian fibroblasts. Using this technology we were able to demonstratethat native 5-HT2A receptors possess significant constitutive, oragonist-independent, receptor activity (U.S. Pat. No. 6,358,698; Weineret. al. J. Pharmacol. Exp. Ther. 2001, 299 (1), 268-276, both of whichare hereby incorporated by reference herein in their entirety, includingany drawings). Furthermore, by directly testing a large number ofcentrally acting medicinal compounds with known clinical activity inneuropsychiatric disease, we determined that compounds withantipsychotic efficacy all shared a common molecular property. Nearlyall of these compounds, which are used by psychiatrists to treatpsychosis, were found to be potent 5-HT2A inverse agonists. This uniqueclinico-pharmacologic correlation at a single receptor subtype iscompelling evidence that 5-HT2A receptor inverse agonism is a molecularmechanism of antipsychotic efficacy in humans.

Detailed pharmacological characterization of a large number ofantipsychotic compounds revealed that they possess broad activity atmultiple related receptor subtypes. Most of these compounds displayagonist, competitive antagonist, or inverse agonist activity at multiplemonoaminergic receptor subtypes, including serotoninergic, dopaminergic,adrenergic, muscarinic and histaminergic receptors. This broad activityis likely responsible for the sedating, hypotensive, and motor sideeffects of these compounds. It would therefore be of great advantage todevelop compounds that are selective inverse agonists of the 5-HT2Areceptor, but which have little or no activity on other monaminereceptors subtypes, especially dopamine D2 receptors. Such compounds maybe useful in the treatment of human disease (e.g., as anti-psychotics),and may avoid the adverse side effects associated with non-selectivereceptor interactions.

U.S. Pat. No. 4,853,394 discloses N-(Hydroxyethylpiperid-4-yl) estersand amides which with gastic motility enhancing, anti-emetic activityand 5-HT antagonist activity.

EP 0 260 070 discloses the acetic acid ester of4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanonefor the alleviation, palliation, mitigation, or inhibition of themanifestations of psychic abnormalities.

SUMMARY OF THE INVENTION

Disclosed herein are compounds of Formula I,

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof,wherein

R¹ is selected from the group consisting of optionally substitutedheterocyclyl, and optionally substituted (heterocyclyl)C₁₋₆-alkyl;

R²and R³ are independently selected from the group consisting ofhydrogen, C₁₋₆-alkyl and halogen or such that R² together with R³ formsa ring;

m is selected from the group consisting of 0, 1, and 2;

n is selected from the group consisting of 1, 2, and 3;

Ar¹ is an optionally substituted aryl or heteroaryl;

W is selected from the group consisting of O and S;

X is selected from the group consisting of optionally substitutedmethylene, optionally substituted ethylene, optionally substitutedpropylene, optionally substituted vinylene, and CH₂N(R^(N)), whereinR^(N) is selected from hydrogen and C₁₋₆-alkyl; and

Ar² is an optionally substituted aryl or heteroaryl.

Also disclosed are methods of inhibiting an activity of a monoaminereceptor comprising contacting the monoamine receptor or a systemcontaining the monoamine receptor with an effective amount of one ormore of the compounds of Formula I. Disclosed are also methods ofinhibiting an activation of a monoamine receptor comprising contactingthe monoamine receptor or a system containing the monoamine receptorwith an effective amount of one or more of the compounds of Formula I.Furthermore, methods of treating psychotic disease using a compound ofFormula I are disclosed.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the current disclosure, the following definitionsshall in their entireties be used to define technical terms, and shallalso, in their entireties, be used to define the scope of thecomposition of matter for which protection is sought in the claims. Theterm “Constitutive activity” is defined as the basal activity of areceptor which is independent of the presence of an agonist.Constitutive activity of a receptor may be measured using a number ofdifferent methods, including cellular (e.g., membrane) preparations(see, e.g., Barr &. Manning, J. Biol. Chem. 272:32979-87 (1997)),purified reconstituted receptors with or without the associatedG-protein in phospholipid vesicles (Cerione et al., Biochemistry23:4519-25 (1984)), and functional cellular assays (U.S. Pat. No.6,358,698).

The term “agonist” is defined as a compound that increases the activityof a receptor when it contacts the receptor.

The term “antagonist” is defined as a compound that competes with anagonist or inverse agonist for binding to a receptor, thereby blockingthe action of an agonist or inverse agonist on the receptor. However, anantagonist (also known as a “neutral” antagonist) has no effect onconstitutive receptor activity.

The term “inverse agonist” is defined as a compound that decreases thebasal activity of a receptor (i.e., signaling mediated by the receptor).Such compounds are also known as negative antagonists. An inverseagonist is a ligand for a receptor that causes the receptor to adopt aninactive state relative to a basal state occurring in the absence of anyligand. Thus, while an antagonist can inhibit the activity of anagonist, an inverse agonist is a ligand that can alter the conformationof the receptor in the absence of an agonist. The concept of an inverseagonist has been explored by Bond et al. in Nature 374:272 (1995). Morespecifically, Bond et al. have proposed that unliganded β₂-adrenoceptorexists in an equilibrium between an inactive conformation and aspontaneously active conformation. Agonists are proposed to stabilizethe receptor in an active conformation. Conversely, inverse agonists arebelieved to stabilize an inactive receptor conformation. Thus, while anantagonist manifests its activity by virtue of inhibiting an agonist, aninverse agonist can additionally manifest its activity in the absence ofan agonist by inhibiting the spontaneous conversion of an unligandedreceptor to an active conformation.

The term “5-HT2A receptor” is defined as a receptor, having an activitycorresponding to the activity of the human serotonin receptor subtype,which was characterized through molecular cloning and pharmacology asdetailed in Saltzman et al., Biochem. Biophys. Res. Comm. 181:1469-78;and Julius et al., Proc. Natl. Acad. Sci. USA 87:928-932.

The term “subject” refers to an animal, preferably a mammal, mostpreferably a human, who is the object of treatment, observation orexperiment.

The term “selective” is defined as a property of a compound whereby anamount of the compound sufficient to effect a desired response from aparticular receptor type, subtype, class or subclass causes asubstantially smaller or no effect upon the activity other receptortypes.

The terms “selectivity” or “selective,” in relation to an inverseagonist, are understood as a property of a compound of the inventionwhereby an amount of compound that effectively inversely agonizes the5-HT2A receptor, and thereby decreases its activity, causes little or noinverse agonistic or antagonistic activity at other, related orunrelated, receptors. In particular, certain compounds of the inventionhave been found not to interact strongly with other serotonin receptors(5-HT 1A, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6, and 7) at concentrations wherethe signaling of the 5-HT2A receptor is strongly or completelyinhibited. Preferably, the compounds of the invention are also selectivewith respect to other monoamine-binding receptors, such as thedopaminergic, histaminergic, adrenergic and muscarinic receptors.Compounds that are highly selective for 5-HT2A receptors may have abeneficial effect in the treatment of psychosis, schizophrenia orsimilar neuropsychiatric disorders, while avoiding adverse effectsassociated with drugs hitherto suggested for this purpose.

The EC₅₀ for an agonist is intended to denote the concentration of acompound needed to achieve 50% of a maximal response seen in R-SAT. Forinverse agonists, EC₅₀ is intended to denote the concentration of acompound needed to achieve 50% inhibition of an R-SAT response frombasal, no compound, levels.

As used herein, the term “coadministration” of pharmacologically activecompounds refers to the delivery of two or more separate chemicalentities, whether in vitro or in vivo. Coadministration refers to thesimultaneous delivery of separate agents; to the simultaneous deliveryof a mixture of agents; as well as to the delivery of one agent followedby delivery of a second agent or additional agents. In all cases, agentsthat are coadministered are intended to work in conjunction with eachother.

In the present context the term “aryl” is intended to mean a carbocyclicaromatic ring or ring system. Moreover, the term “aryl” includes fusedring systems wherein at least two aryl rings, or at least one aryl andat least one C₃₋₈-cycloalkyl share at least one chemical bond. Someexamples of “aryl” rings include optionally substituted phenyl,naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl,indenyl, and indanyl. The term “aryl” relates to aromatic, preferablybenzenoid groups, connected via one of the ring-forming carbon atoms,and optionally carrying one or more substituents selected fromheterocyclyl, heteroaryl, halo, hydroxy, amino, cyano, nitro,alkylamido, acyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkylamino, alkylsulfenyl, alkylsulfinyl,alkylsulfonyl, sulfamoyl, or trifluoromethyl. The aryl group may besubstituted at the para and/or meta positions. Representative examplesof aryl groups include, but are not limited to, phenyl, 3-halophenyl,4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl,4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-trifluoromethoxyphenyl 3-cyanophenyl, 4-cyanophenyl,dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl,trifluoromethylphenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl,4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and4-(2-oxopyrrolidin-1-yl)phenyl.

In the present context, the term “heteroaryl” is intended to mean aheterocyclic aromatic group where one or more carbon atoms in anaromatic ring have been replaced with one or more heteroatoms selectedfrom the group comprising nitrogen, sulfur, phosphorous, and oxygen.

Furthermore, in the present context, the term “heteroaryl” comprisesfused ring systems wherein at least one aryl ring and at least oneheteroaryl ring, at least two heteroaryl rings, at least one heteroarylring and at least one heterocyclyl ring, or at least one heteroaryl ringand at least one C₃₋₈-cycloalkyl ring share at least one chemical bond.

The term “heteroaryl” is understood to relate to aromatic, C₃₋₈ cyclicgroups further containing one oxygen or sulfur atom or up to fournitrogen atoms, or a combination of one oxygen or sulfur atom with up totwo nitrogen atoms, and their substituted as well as benzo- andpyrido-fused derivatives, preferably connected via one of thering-forming carbon atoms. Heteroaryl groups may carry one or moresubstituents, selected from halo, hydroxy, amino, cyano, nitro,alkylamido, acyl, C₁₋₆-alkoxy, C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl,C₁₋₆-aminoalkyl, C₁₋₆-alkylamino, alkylsulfenyl, alkylsulfinyl,alkylsulfonyl, sulfamoyl, or trifluoromethyl. In some embodiments,heteroaryl groups may be five- and six-membered aromatic heterocyclicsystems carrying 0, 1, or 2 substituents, which may be the same as ordifferent from one another, selected from the list above. Representativeexamples of heteroaryl groups include, but are not limited to,unsubstituted and mono- or di-substituted derivatives of furan,benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole,oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole,isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole,quionoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine,which are all preferred, as well as furazan, 1,2,3-oxadiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole,pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine,cinnoline, phthalazine, quinazoline, and quinoxaline. In someembodiments, the substituents are halo, hydroxy, cyano, O—C₁₋₆-alkyl,C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, amino-C₁₋₆-alkyl.

In the present context, the term “alkyl” and “C₁₋₆-alkyl” are intendedto mean a linear or branched saturated hydrocarbon chain wherein thelongest chain has from one to six carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, and hexyl. An alkyl chain may be optionallysubstituted.

The term “heterocyclyl” is intended to mean three-, four-, five-, six-,seven-, and eight-membered rings wherein carbon atoms together with from1 to 3 heteroatoms constitute said ring. A heterocyclyl may optionallycontain one or more unsaturated bonds situated in such a way, however,that an aromatic i-electron system does not arise. The heteroatoms areindependently selected from oxygen, sulfur, and nitrogen.

A heterocyclyl may further contain one or more carbonyl or thiocarbonylfunctionalities, so as to make the definition include oxo-systems andthio-systems such as lactams, lactones, cyclic imides, cyclicthioimides, cyclic carbamates, and the like.

Heterocyclyl rings may optionally also be fused to aryl rings, such thatthe definition includes bicyclic structures. Preferred such fusedheterocyclyl groups share one bond with an optionally substitutedbenzene ring. Examples of benzo-fused heterocyclyl groups include, butare not limited to, benzimidazolidinone, tetrahydroquinoline, andmethylenedioxybenzene ring structures.

Some examples of “heterocyclyls” include, but are not limited to,tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane. Binding to the heterocycle may be at the position of aheteroatom or via a carbon atom of the heterocycle, or, for benzo-fusedderivatives, via a carbon of the benzenoid ring.

The term “(heterocyclyl)C₁₋₆-alkyl” is understood as heterocyclyl groupsconnected, as substituents, via an alkyl, each as defined herein. Theheterocyclyl groups of (heterocyclyl)C₁₋₆-alkyl groups may besubstituted or unsubstituted. The term “(heterocyclyl)C₁₋₆-alkyl” isintended to mean an alkyl chain substituted at least once with aheterocyclyl group, typically at the terminal position of the alkylchain.

In the present context, the term “C₂₋₈-alkenyl” is intended to mean alinear or branched hydrocarbon group having from two to eight carbonatoms and containing one or more double bonds. Some examples ofC₂₋₈-alkenyl groups include allyl, homo-allyl, vinyl, crotyl, butenyl,pentenyl, hexenyl, heptenyl and octenyl. Some examples of C₂₋₈-alkenylgroups with more than one double bond include butadienyl, pentadienyl,hexadienyl, heptadienyl, heptatrienyl and octatrienyl groups as well asbranched forms of these. The position of the unsaturation (the doublebond) may be at any position along the carbon chain.

In the present context the term “C₂₋₈-alkynyl” is intended to mean alinear or branched hydrocarbon group containing from two to eight carbonatoms and containing one or more triple bonds. Some examples ofC₂₋₈-alkynyl groups include ethynyl, propynyl, butynyl, pentynyl,hexynyl, heptynyl and octynyl groups as well as branched forms of these.The position of unsaturation (the triple bond) may be at any positionalong the carbon chain. More than one bond may be unsaturated such thatthe “C₂₋₈-alkynyl” is a di-yne or enedi-yne as is known to the personskilled in the art.

In the present context, the term “C₃₋₈-cycloalkyl” is intended to coverthree-, four-, five-, six-, seven-, and eight-membered rings comprisingcarbon atoms only. A C₃₋₈-cycloalkyl may optionally contain one or moreunsaturated bonds situated in such a way, however, that an aromaticπ-electron system does not arise.

Some examples of preferred “C₃₋₈-cycloalkyl” are the carbocyclescyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene,cycloheptane, cycloheptene.

The terms “(aryl)C₁₋₆-alkyl” is intended to mean an aryl groupconnected, as a substituent, via a C₁₋₆-alkyl, each as defined herein.The aryl groups of (aryl)C₁₋₆-alkyl may be substituted or unsubstituted.Examples include benzyl, substituted benzyl, 2-phenylethyl,3-phenylpropyl, and naphthylalkyl.

The terms “(cycloalkyl)C₁₋₆-alkyl” is intended to mean a cycloalkylgroups connected, as substituents, via an alkyl, each as defined herein.

When used herein, the term “O—C₁₋₆-alkyl” is intended to meanC₁₋₆-alkyloxy, or alkoxy, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,isopentyloxy, neopentyloxy and hexyloxy

The term “halogen” includes fluorine, chlorine, bromine and iodine.

In the present context, i.e. in connection with the terms “C₁₋₆-alkyl”,“aryl”, “heteroaryl”, “heterocyclyl”, “C₃₋₈-cycloalkyl”,“heterocyclyl(C₁₋₆-alkyl)”, “(cycloalkyl)alkyl”, “O—C₁₋₆-alkyl”,“C₂₋₈-alkenyl”, and “C₂₋₈-alkynyl”, the term “optionally substituted” isintended to mean that the group in question may be substituted one orseveral times, such as 1 to 5 times, or 1 to 3. times, or 1 to 2 times,with one or more groups selected from C₁₋₆-alkyl, C₁₋₆-alkoxy, oxo(which may be represented in the tautomeric enol form), carboxyl, amino,hydroxy (which when present in an enol system may be represented in thetautomeric keto form), nitro, alkylsulfonyl, alkylsulfenyl,alkylsulfinyl,C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl, formyl, amino,mono- and di(C₁₋₆-alkyl)amino; carbamoyl, mono- anddi(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,C₁₋₆-alkylhydroxyimino, cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy,C₁₋₆-alkylsulphonyloxy, dihaloger-C₁₋₆-alkyl, trihalogen-C₁₋₆-alkyl,heterocyclyl, heteroaryl, and halo. In general, the above substituentsmay be susceptible to further optional substitution.

The term “salts” is intended to mean pharmaceutically acceptable acidaddition salts obtainable by treating the base form of a functionalgroup, such as an amine, with appropriate acids such as inorganic acids,for example hydrohalic acids; typically hydrochloric, hydrobromic,hydrofluoric, or hydroiodic acid; sulfuric acid; nitric acid; phosphoricacid and the like; or organic acids, for example acetic, propionic,hydroacetic, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic,propanedioic, butanedioic, (Z)-2-butenedioic, (E)-butenedioic,2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic acid, cyclohexanesulfamic,2-hydoxybenzoic, 4-amino-2-hydroxybenzoic, and other acids known to theskilled practitioner.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs are inactivederivatives of the compounds of this invention that are readilyconvertible in vivo into the required compound. Conventional proceduresfor the selection and preparation of suitable prodrug derivatives aredescribed, for example, in Design of Prodrugs, (ed. H. Bundgaard,Elsevier, 1985). Metabolites of these compounds include active speciesthat are produced upon introduction of compounds of this invention intothe biological milieu.

Where the compounds according to the invention have at least one chiralcenter, they may exist as a racemate or as enantiomers. It should benoted that all such isomers and mixtures thereof are included in thescope of the present invention. Furthermore, some of the crystallineforms for compounds of the present invention may exist as polymorphs andas such are intended to be included in the present invention. Inaddition, some of the compounds of the present invention may formsolvates with water (i.e., hydrates) or common organic solvents. Suchsolvates are also included in the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, such isomers maybe separated by conventional techniques such as preparative chiralchromatography. The compounds may be prepared in racemic form orindividual enantiomers may be prepared by stereoselective synthesis orby resolution. The compounds may be resolved into their componentenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (-)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolvedusing a chiral auxiliary by formation of diastereomeric derivatives suchas esters, amides or ketals followed by chromatographic separation andremoval of the chiral auxiliary.

The compounds of the present invention are effective upon administrationorally. In vivo experiments performed in rodents have indicated that alower dose of the compounds of the present invention results in equal orimproved behavioral responses in animal models of psychosis. Theseresults are indicative of a higher bioavailability of the compounds ofthe present invention, compared to the compounds disclosed in the priorart. An improved bioavailability is corroborated by the observation thatthe new compounds presented herein are not significantly more potentwhen assayed for their effects on serotonin receptors in vitro, and yetrepresent a substantial improvement when orally administered. The highlyimproved efficacy observed after oral dosing is probably a result ofincreased metabolic stability, improved physicochemical properties, suchas solubility or chemical stability, or different pharmacokineticcharacteristics, such as distribution, permeability, or the like.Without being bound to a particular theory, it is reasonable to ascribesuch differences to the presence of a heterocyclic substituent at thenitrogen of the piperidine ring of these compounds. The presence of sucha heterocyclic substituent could affect the behavior of thesederivatives in terms of solubility and/or metabolic lability. Thepresence of heteroatoms in substituents close to the nitrogen would alsobe suspected to influence the basicity of the nitrogen, which, in turn,might affect properties such as distribution (Log D) or metabolism.

Generally, a high degree of bioavailability of any pharmaceutical isconsidered highly beneficial. This relates primarily to the ability tobe able to administer an efficacious yet safe dose of the drug to allsubjects irrespective of their potential predisposition topolymorphism-dependent drug metabolism. Examples of many suchpolymorphisms are well known in the art. Thus, a drug which undergoessubstantial metabolism, either during its first pass through the liveror in the gastrointestinal tract, will display a relatively low, andsometimes dose-dependent, bioavailability measured as the plasmaconcentration achieved after peroral distribution. Inter-individualdifferences in drug exposure are generally more severe when a drug isheavily metabolized, and, as a consequence, displays low oralbioavailability. Subjects with polymorphisms resulting in changes in theactivity of drug-metabolizing enzymes are likely to become exposed tovery different (normally much higher) plasma levels than thosedisplaying a normal metabolic activity. Hence, aspects of the presentinvention relate to novel compounds which display characteristicssuggestive of superior drug properties when compared to those previouslyknown in the art.

In general, compounds of Formula I are active at monoamine receptors,specifically serotonin receptors. Several compounds of the inventionshare the common property of acting as inverse agonists at the 5-HT2Areceptor. Thus, experiments performed on cells transiently expressingthe human phenotype of said receptor have shown that the compounds ofgeneral Formula I attenuate the signaling of such receptors in theabsence of additional ligands acting upon the receptor. The compoundshave thus been found to possess intrinsic activity at this receptor andare able to attenuate the basal, non-agonist-stimulated, constitutivesignaling responses that the 5-HT2A receptor displays. The observationthat the compounds of general Formula I are inverse agonists alsoindicates that these compounds have the ability to antagonize theactivation of 5-HT2A receptors that is mediated by endogenous agonistsor exogenous synthetic agonist ligands.

In certain embodiments, the present invention provides compounds thatshow a relatively high degree of selectivity towards the 5-HT2A subtypeof serotonin receptors relative to other subtypes of the serotonin(5-HT) family of receptors as well as to other receptors, mostparticularly the monoaminergic G-protein coupled receptors, such asdopamine receptors. In other embodiments, the compounds of the presentinvention act as inverse agonists at the 5-HT2A subtype of serotoninreceptors.

The compounds of general Formula I may therefore be useful for treatingor alleviating symptoms of disease conditions associated with impairedfunction, in particular elevated levels of activity, of especially5-HT2A receptors, whether this impaired function is associated withimproper levels of receptor stimulation or phenotypical aberrations.

Others have previously hypothesized that certain neuropsychologicaldiseases might be caused by altered levels of constitutive activity ofmonoamine receptors. Such constitutive activity might be modified viacontacting the relevant receptor with a synthetic inverse agonist. Bydirectly testing a large number of centrally acting medicinal compoundswith known clinical activity in neuropsychiatric disease, we determinedthat compounds with antipsychotic efficacy all shared a common molecularproperty. Nearly all of these compounds that are used by psychiatriststo treat psychosis were found to be potent 5-HT2A inverse agonists. Thiscorrelation is compelling evidence that 5-HT2A receptor inverse agonismis a molecular mechanism of antipsychotic efficacy in humans.

Detailed pharmacological characterization of a large number ofantipsychotic compounds in our laboratory revealed that they possessbroad activity at multiple related receptor subtypes. Most of thesecompounds display either agonist, competitive antagonist, or inverseagonist activity at multiple monoaminergic receptor subtypes includingserotoninergic, dopaminergic, adrenergic, muscarinic and histaminergicreceptors. This broad activity is likely responsible for the sedating,hypotensive, and motor side effects of these compounds. It follows thatthe compounds disclosed herein will possess efficacy as, for example,novel antipsychotics, but will have fewer or less severe side effectsthan existing compounds.

Thus, in the first aspect, the present invention relates to a compoundof Formula I,

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof,wherein

R¹ is selected from the group consisting of optionally substitutedheterocyclyl, and optionally substituted (heterocyclyl)C₁₋₆-alkyl;

R² and R³ are independently selected from the group consisting ofhydrogen, C₁₋₆-alkyl and halogen or such that R² together with R³ formsa ring;

m is selected from the group consisting of 0, 1, and 2;

n is selected from the group consisting of 1, 2, and 3;

Ar¹ is an optionally substituted aryl or heteroaryl;

W is selected from the group consisting of O and S;

X is selected from the group consisting of optionally substitutedmethylene, optionally substituted ethylene, optionally substitutedpropylene, optionally substituted vinylene, and CH₂N(R^(N)), whereinR^(N) is selected from hydrogen and C₁₋₆-alkyl; and

Ar² is an optionally substituted aryl or heteroaryl.

As discussed, the presence of a heterocyclic substituent at the nitrogenof the piperidine ring of these compounds is considered to improve thebioavailability of the compounds, in comparison to related compoundsknown to the person skilled in the art.

In some embodiments, the heterocyclyl or (heterocyclyl)C₁₋₆-alkyl of R¹may be optionally substituted. The substituent may be selected fromhalogen, hydroxy, alkyl, alkoxy, and amino. In some embodiments, thesubstituent may be on the alkyl chain or the ring system. In furtherembodiments the substituent is on the ring system.

In certain embodiments, the heterocyclyl ring in R¹ may be selected fromthe group consisting of tetrahydrothiopyran, 4H-pyran, tetrahydropyran,piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane,isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone,thiazoline, thiazolidine, and 1,3-oxathiolane. In some embodiments, theheterocyclyl ring is selected from 1,3-dioxane, 1,3-dioxolane, andtetrahydropyran.

The azacyclic ring may be a 5, 6, or 7-membered ring as reflected inthat m may be selected from 0, 1 and 2. In certain embodiments, however,the azacyclic ring is a 6-membered ring, wherein m is 1.

The azacyclic ring, further to being substituted at the nitrogenposition, may be substituted with R² and R³. R² and R³ may beindependently selected from the group consisting of hydrogen,C₁₋₆-alkyl, and halogen, or such that R² together with R³ forms a ring.That is to say that R² and R³ may be biradicals which combine to form a3-, 4-, 5-, 6-, or 7-membered ring system with the atoms of theazacyclic ring.

In some embodiments, the azacyclic ring system is selected from

wherein R⁷ and R⁸ are independently selected from the group consistingof hydrogen, halogen, hydroxyl, and C₁₋₆ alkyl. In certain embodimentsR⁷ and R⁸ are hydrogen.

In other embodiments, R² and R³ are hydrogen.

In some embodiments, R¹ is an optionally substituted(heterocyclyl)C₁₋₆-alkyl. In certain of these embodiments, R¹ is anoptionally substituted (heterocyclyl)methyl, an optionally substituted(heterocyclyl)ethyl, or an optionally substituted (heterocyclyl)propyl.In other embodiments, R¹ is an optionally substituted(heterocyclyl)ethyl.

Ar¹ is linked to a central nitrogen atom via a short aliphatic chain 1,2, or 3 carbon atoms in length. In certain embodiments, n is 1,resulting in a methylene spacer between the central nitrogen atom andAr¹. Ar¹ may be an optionally substituted aryl or heteroaryl. In someembodiments, Ar¹ is an optionally substituted aryl. In some embodiments,the central nitrogen atom is linked to an optionally substituted benzylgroup.

In certain embodiments Ar¹ is an optionally substituted aryl, which maybe a 4-substituted aryl. The 4-substituent of the 4-substituted aryl maybe any substituent known to the person skilled in the art, such as aC₁₋₆-alkyl, C₁₋₆-alkoxy, carboxyl, amino, hydroxy, thiol, nitro, cyano,guanidino, carbamido and halogen. In some embodiments, the halogen isfluoro, while in other embodiments, the halogeni s chloro.

In other embodiments, Ar¹ is selected from the group consisting ofalkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substitutedphenyl, hydroxy-substituted phenyl and amino-substituted phenyl. In someembodiments, the substituent may be present 0 to 5 times, or 0 to 4times, or 0 to 3 times, such as 0, 1, 2, or 3 times. In certainembodiments, the substituent is present 1 to 2 times. In someembodiments, Ar¹ is a 4-substituted aryl selected from the groupconsisting of 4-halophenyl and 4-alkylphenyl. In some embodiments, thephenyl group is 4-fluorophenyl.

In other embodiments, Ar¹ is an optionally substituted heteroaryl. Theheteroaryl may be substituted with substituents known to the personskilled in the art, such as a C₁₋₆-alkyl, C₁₋₆-alkoxy, carboxyl, amino,hydroxy, thiol, nitro, cyano, guanidino, carbamido and halogen.

Further to being linked to both the azacyclic ring and to Ar¹ via ashort aliphatic chain, the central nitrogen is linked to Ar² via a 2 to4 carbon spacer unit. This spacer unit comprises a carbonyl orthiocarbonyl function wherein W is selected from the group consisting ofoxygen and sulfur. In some embodiments W is oxygen.

In certain embodiments, X may be selected from the group consisting ofoptionally substituted methylene, optionally substituted ethylene,optionally substituted propylene, optionally substituted vinylene, andCH₂N(R^(N)). Thus X may extend the spacer unit by 1 to 3 atoms betweenthe central nitrogen and Ar² and render the central nitrogen part of anamide or carbamide. In some embodiments, X is selected from the groupconsisting of optionally substituted methylene, optionally substitutedethylene, and CH₂N(R^(N)). In some embodiments, X is an optionallysubstituted methylene, or CH₂N(R^(N)), wherein R^(N) may be hydrogen.

In certain embodiments, Ar² may be an optionally substituted aryl orheteroaryl. In certain embodiments, Ar² is an optionally substitutedaryl. In some embodiments, Ar² is a 4-substituted aryl.

In a further embodiment, Ar² may be selected from the group consistingof alkoxy-substituted phenyl, halogen-substituted phenyl,hydroxy-substituted phenyl, amino-substituted phenyl, andheterocyclyl-substituted phenyl.

In certain embodiments, Ar² is a 4-substituted aryl wherein thesubstituent is selected from the group consisting of alkyl, alkoxy,halogen, hydroxy, amino, alkylamino, heterocyclyl, and heteroaryl. Insome embodiments, the substituent on Ar² is selected from chloro,fluoro, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, trifluoromethoxy, N-morpholinyl,N-pyrrolidinyl, N-pyrazolyl, N-triazolyl and 2-oxopyrrolidinyl.

In another aspect, the present invention relates to a compound selectedfrom the group consisting of

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isobutoxybenzyl)carbamide,hydrochloride;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-hydroxy-2-methylpropoxy)phenyl]acetamide,tartrate;

N-{1-[3-(3,5-Dimethylpiperidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,dihydrochloride;

1-[3-(4-{(4-Fluorobenzyl)-[2-(4-isobutoxyphenyl)acetyl]amino}piperidin-1-yl)propyl]piperidine-4-carboxylicacid methyl ester, dihydrochloride;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1-methylpyrrolidin-2-yl)ethyl]piperidin-4-yl}acetamide,dioxalate;

N-{1-[3-(2,6-Dimethylmorpholin-4-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,dioxalate;

N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxypiperidin-1-yl)propyl]piperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide,dioxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[3-(2-methylpiperidin-1-yl)propyl]piperidin-4-yl}acetamide,dioxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-[1-(3-pyrrolidin-1-yl-propyl)piperidin-4-yl]acetamide,dioxalate;

N-{1-[3-(2,5-Dimethylpyrrolidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,dioxalate;

N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxymethylpiperidin-1-yl)propyl]piperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide,dioxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate;

N-[2-(4-Fluorophenyl)ethyl]-2-(4-isobutoxyphenyl}N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate;

N-[2-(4-Fluorophenyl)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide,oxalate;

N-(4-Fluorobenzyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide,oxalate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)acetamide,oxalate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-2-(4-propoxyphenyl)acetamide,oxalate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide,tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isobutoxybenzyl)carbamide,tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-p-tolylacetamide,tartrate;

2-Benzofuran-5-yl-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate;

2-(2,3-Dihydrobenzofuran-5-yl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate;

N-{1-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethylphenyl)acetamide,tartrate;

2-(4-Cyanophenyl}N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide,hydrochloride;

2-(4-Methoxyphenyl}N-(4-methylbenzyl}N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide,hydrochloride;

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide,hydrochloride;

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-{1-[3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)propyl]piperidin-4-yl}acetamide;hydrochloride;

N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-2-(4-methoxyphenyl}N-(4-methylbenzyl)acetamide,hydrochloride;

2-(4-Methoxyphenyl}N-(4-methylbenzyl}N-{1-[3-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)propyl]piperidin-4-yl}-acetamide,hydrochloride;

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-{1-[4-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)butyl]piperidin-4-yl}acetamide,hydrochloride;

N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)acetamide,hydrochloride;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isopropoxy-benzyl)carbamide,oxalate;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl]-2-(4-methoxyphenyl}N-(4-methylbenzyl)acetamide,hydrochloride;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,hydrochloride;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-isopropoxyphenyl}N-(4-methylbenzyl)acetamide,hydrochloride;

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide,tartrate;

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidin-4-yl}carbamide,oxalate;

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-[1-(3-morpholin-4-yl-propyl)piperidin-4-yl]carbamide,oxalate;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholin-4-ylethyl)piperidin-4-yl]acetamide,dihydrochloride;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)N-[1-(3-morpholin-4-ylpropyl)piperidin-4-yl]acetamide,dihydrochloride;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(3-morpholin-4-ylpropyl)piperidin-4-yl]acetamide,dihydrochloride;

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-[1-(3-morpholin-4-yl-propyl)piperidin-4-yl]acetamide,dihydrochloride;

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-[1-(3-piperidin-1-yl-propyl)piperidin-4-yl]carbamide,oxalate;

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-[1-(3-((S)-4-isopropyl-2-oxazolidinon-1-yl-propyl)piperidin-4-yl]carbamide,tartrate;

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]}piperidin-4-yl]carbamide,oxalate;

N-{1-[3-(1,3-Dioxolan-2-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isopropoxybenzyl)carbamide, oxalate;

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-N′-(4-isopropoxybenzyl)carbamide,oxalate;

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{[2-(1-methylpyrrolidin-2-yl)ethyl]-piperidin-4-yl}carbamide, oxalate;

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate;

N-[1-(1,3-Dioxan-5-yl)-piperidin-4-yl)-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate:

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxyphenyl)acetamide,tartrate:

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide,tartrate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]acetamide,tartrate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-[1-(tetrahydropyran-4-ylmethyl)piperidin-4-yl]acetamide,tartrate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl]acetamide,tartrate;

N-(4-Fluorobenzyl)-2-(4-fluorophenyl)-N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]acetamide,tartrate;

N-[1-((S)-3,5-Dihydroxypentyl)piperidine-4-yl]-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;

N-{1-[2-((4S)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;

2-(4-Benzyloxyphenyl}N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-hydroxyphenylacetamide,tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-methoxyphenylacetamide,tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropylphenyl)acetamide,tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxy-phenyl)acetamide,tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-ethoxyphenyl)-acetamide,oxalate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)acetamide,oxalate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-phenylacetamide,oxalate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-fluoroethoxy)-phenyl]acetamide,oxalate;

N-{1-[2-(5,5-Dimethyl-1,3dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide, oxalate;

N-{1-[2-(4,6-Dimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate;

N-(4-Fluorobenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide, oxalate;

N-(4-Fluorobenzyl)-2-(4-isopropylphenyl)-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate;

N-(4-Fluorobenzyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide, oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}acetamide, oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(1,3-dioxolan-2-yl)propyl]piperidin-4-yl}acetamide,tartrate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-(3-piperidin-1-yl-propyl)piperidin-4-yl}-acetamide,dihydrochloride;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-piperidin-4-yl}acetamide,oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-piperidin-1-yl)propyl]piperidin-4-yl}acetamide;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-pyrrolidin-1-yl)propyl]piperidin-4-yl}acetamide,hydrochloride;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-methyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,tartrate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-{1-[3-((S)-4-ethyl-2-oxo-oxazolidin-3-yl)-propyl]piperidin-4-yl}acetamide,oxalate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1,3-oxothiolan-2-yl)ethyl]piperidin-4-yl}acetamide,L-tartrate;

2-(4-Bromophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutylamino-phenyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propylamino-phenyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-(1-nitropropyl)-phenyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-oxopyrrolidin-1-yl)phenyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutylsulfanyl-phenyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iodophenyl)-acetamide,L-tartrate;

2-(4-Acetophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-acetamide,L-tartrate;

2-[4-(1-Hydroxyiminoethyl)phenyl}N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-morpholin-4-yl-phenyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyrazol-1-yl-phenyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-2-yl)-1-methylethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iso-butoxyphenyl)acetamide,L-tartrate;

N-{1-[2-(1,3-Dioxan-4-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyrazol-1-yl-phenyl)acetamide,L-tartrate;

N-{1-[2-((4R)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate; and

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(1,2,4-triazol-4-yl)phenyl]acetamide,L-tartrate.

As stated, the present inventors have found that compounds of Formula Iare effective modulators of the 5-HT2A subtype of human serotoninreceptors. The invention thus further relates to a method of inhibitingan activity of a monoamine receptor comprising contacting the monoaminereceptor or a system containing the monoamine receptor with an effectiveamount of one or more of the compounds as defined herein. The monoaminereceptor may be a serotonin receptor, typically of the 5HT2A subclass.

The serotonin receptor may alternatively be in the central nervoussystem or in the peripheral nervous system. Typically, the serotoninreceptor may be in blood cells or platelets. In certain embodiments, theserotonin receptor may be mutated or modified.

The activity of a monoamine receptor that is modulated may typically besignaling activity. Moreover, the activity may typically beconstitutive. The activity associated with serotonin receptor maytypically be activation.

In another aspect, the present invention relates to a method ofinhibiting an activation of a monoamine receptor comprising contactingthe monoamine receptor or a system containing the monoamine receptorwith an effective amount of one or more of the compounds as definedherein. The activation, which may be inhibited by the method of theinvention, may typically be an activation resulting from an agonisticagent. The agonistic agent may be exogenous or the agonistic agent maybe endogenous. Moreover, the activation may be constitutive.

Another aspect of the present invention relates to the treatment ofdisease conditions associated with dysfunction of a monoamine receptorand to the use of a compound of Formula I for the preparation of amedicament for the treatment of a disease condition associated with amonoamine receptor. The disease condition may be associated withactivation of a monoamine receptor, such as associated with increasedactivity of monoamine receptor.

In yet another aspect, the present invention relates to a method oftreating schizophrenia comprising administering to a subject in need ofsuch treatment a therapeutically effective amount of a compound ofFormula I, as defined herein. Alternatively stated, the inventionrelates, in part, to the use of a compound of Formula I for thepreparation of a medicament for the treatment of schizophrenia. Afurther aspect relates to a method of treating migraine comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula I. Alternatively stated, theinvention relates, in part, to the use of a compound of Formula I forthe preparation of a medicament for the treatment of migraine. A furtheraspect of the invention relates to a method of treating psychosiscomprising administering to a subject in need of such treatment atherapeutically effective amount of a compound of Formula I.Alternatively stated, the invention relates, in part, to the use of acompound of Formula I for the preparation of a medicament for thetreatment of psychosis. A still further aspect of the invention relatesto a method of treating psychotic symptoms, such as hallucinations,consequent of administration of dopamine agonists, such as L-dopa, toindividuals in need of treatment, such as people suffering fromParkinson's comprising administering a compound of Formula I.Alternatively stated, the invention relates, at least in part, to theuse of a compound of Formula I for the preparation of a medicament forthe treatment of psychotic symptoms, such as hallucinations, consequentof administration of dopamine agonists, such as L-dopa, to individualsin need of treatment, such as people suffering from Parkinson's disease.

Another aspect of the present invention relates to a method of treatinga disease condition associated with a monoamine receptor comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of one or more of the compound of Formula I, as definedherein. The disease condition may be selected from the group consistingof schizophrenia, schizoaffective disorders; psychosis and relatedbehavioral abnormalities observed with neurodegenerative disordersincluding Parkinson's, Alzheimer's disease, Lewy Body Dementia,Frontotemporal Dementia, Huntington's disease, and SpinocerebellarAtrophy; drug induced psychosis including side effects observed withselective serotonin reuptake inhibitor (SSRI) treatment of chronicneurodegenerative disorders such as Alzheimer's, Parkinson's andHuntington's disease; Reynaud's Phenomena; migraine; hypertension;thrombosis; vasospasm; ischemia; depression; anxiety; “motor tics”;Tourette's syndrome; dyskinesias, on/off phenomena, tremor, rigidity,bradykinesia, psychomotor slowing, addiction, including alcoholaddiction, opioid addiction, and nicotine addiction; sleep disorders;appetite disorders; decreases in libido and ejaculatory problems. Thus,the invention thus relates to the use of a compound of Formula I, asdefined herein, for the preparation of a medicament for the for thetreatment of diseases and conditions selected from the group consistingof schizophrenia, schizoaffective disorders; psychosis and relatedbehavioural abnormalities observed with neurodegenerative disordersincluding Parkinson's, Alzheimer's disease, Lewy Body Dementia,Frontotemporal Dementia, Huntington's disease, and SpinocerebellarAtrophy; drug induced psychosis including side effects observed withSSRI treatment of chronic neurodegenerative disorders such asAlzheimer's, Parkinson's and Huntington's disease; Reynaud's Phenomena;migraine; hypertension; thrombosis; vasospasm; ischemia; depression;anxiety; “motor tics”; Tourette's syndrome; dyskinesias, on/offphenomena, tremor, rigidity, bradykinesia, psychomotor slowing,addiction, including alcohol addiction, opioid addiction, and nicotineaddiction; sleep disorders; appetite disorders; decreases in libido andejaculatory problems.

Another aspect of the present invention relates to the treatment of druginduced psychosis and the treatment of side effects observed with SSRItreatment behavioural aspects of chronic neurodegenerative disorders,typically to the treatment of psychotic symptoms, such ashallucinations, consequent of administration of dopamine agonists, suchas L-dopa, to individuals in need of treatment, such as people sufferingfrom Parkinson's.

Similarly, aspects of the invention relate to a method for the treatmentof diseases and conditions as described herein comprising administeringan adjunctive or therapeutic amount of one or more of the compound ofFormula I. The invention thus relates to the use of a compound ofFormula I for the preparation of a medicament for the treatment ofdiseases and conditions as described herein wherein the compound ofFormula I is the sole active agent in the medicament or is an adjunctivewherein the medicament further comprises an agent known to the personskilled in the art for the treatment of said diseases and conditions.

Other aspects of the invention relate to pharmaceutical compositionscomprising an effective amount of a compound of general Formula I.Compounds of the present invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever specific pharmacological modification of the activityof monoamine receptors is required.

Aspects of the present invention also provide pharmaceuticalcompositions comprising one or more compounds of the invention togetherwith a pharmaceutically acceptable diluent or excipient. Preferably suchcompositions are in unit dosage forms such as tablets, pills, capsules(including sustained-release or delayed-release formulations), powders,granules, elixirs, tinctures, syrups and emulsions, sterile parenteralsolutions or suspensions, aerosol or liquid sprays, drops, ampoules,auto-injector devices or suppositories; for oral, parenteral (e.g.,intravenous, intramuscular or subcutaneous), intranasal, sublingual orrectal administration, or for administration by inhalation orinsufflation, and may be formulated in an appropriate manner and inaccordance with accepted practices such as those disclosed inRemington's Pharmaceutical Sciences, (Gennaro, ed., Mack Publishing Co.,Easton Pa., 1990, herein incorporated by reference). Alternatively, thecompositions may be in sustained-release form suitable for once-weeklyor once-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. The present inventionalso contemplates providing suitable topical formulations foradministration to, e.g., eye or skin or mucosa.

A further aspect of the invention relates to a method for identifying agenetic polymorphism predisposing a subject to being responsive to oneor more of the compounds of Formula I, as defined herein, comprising:

administering to a subject a therapeutically effective amount of thecompound;

measuring the response of said subject to said compound, therebyidentifying a responsive subject having an ameliorated disease conditionassociated with a monoamine receptor; and identifying a geneticpolymorphism in the responsive subject, wherein the genetic polymorphismpredisposes a subject to being responsive to the compound. Theameliorated disease condition is typically associated with the 5-HTclass or 5-HT2A subclass of monoaminergic receptors.

A further aspect of the invention relates to a method for identifying asubject suitable for treatment with one or more of the compounds ofFormula I, comprising detecting the presence of a polymorphism in asubject wherein the polymorphism predisposes the subject to beingresponsive to the compound, and wherein the presence of the polymorphismindicates that the subject is suitable for treatment with one or more ofthe compounds of Formula I.

Methods of Preparation

The compounds in accordance with the present invention may besynthesized by methods described below, or by modification of thesemethods. Ways of modifying the methodology include, among others,temperature, solvent, reagents etc, and will be obvious to those skilledin the art.

For instance, compounds of the formula C may be synthesized from thecorresponding ketone A by reductive amination utilizing any primaryamine. The reaction is conveniently carried out by stirring thereactants in an inert solvent such as methanol or ethanol containingacetic acid. As reducing agent NaBH₄, NaCNBH₃, BH₃.pyridine or anyrelated reagent may be used including solid-supported reagents. Thereaction is typically carried out at room temperature. The ketone A, asexemplified by the piperidone, may be chosen from a list of compoundscorresponding to the Z-group listed in formula (I). The ketones caneither be obtained commercially or synthesized by methodology disclosedin Lowe et al. J Med. Chem. 37: 2831-40 (1994); Carroll et al. J. Med.Chem. 35:2184-91 (1992); or Rubiralta et al. Piperidine—Structure,Perparation, Reactivity and Synthetic Applications of Piperidine and itsDerivatives. (Studies in Organic Chemistry 43, Elsevier, Amsterdam,1991). The protecting group P includes groups such as those described inT. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry,3. Ed. John Wiley & Sons, 1999, and they should be chosen in such a way,that they are stable to the reaction conditions applied and readilyremoved at a convenient stage using methodology known from the art.Typical protecting groups are N-Boc, N-Cbz, N-Bn.

Alternatively, the amine C can be synthesized from the primary amine Bby reductive amination with any aldehyde. The reaction is convenientlycarried out by stirring the reactants in an inert solvent such asmethanol or ethanol containing acetic acid. As reducing agent NaBH₄,NaCNBH₃, BH₃-pyridine or any related reagent may be used includingsolid-supported reagents. The reaction is typically carried out at roomtemperature. The primary amine B, as exemplified by the4-aminopiperidine, may be chosen from a list of compounds correspondingto the Z-groups listed in formula (I). The amines can either be obtainedcommercially or synthesized from the corresponding ketones. Theprotecting group P may be chosen as stated above.

Alternatively, the amine C can be synthesized from the primary amine Bby alkylation with any alkylating agent (R-L₁). The leaving group L₁ issuitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g.tosylate or mesylate, or another leaving group favoring the reaction.The reaction is conveniently carried out by stirring the reagents underbasic conditions in an inert solvent, e.g., diisopropylethylamine inacetonitrile, or K₂CO₃ in N,N-dimethylformamide. The reaction istypically carried out at temperatures between room temperature and 80°C. The primary amine B, as exemplified by the 4-aminopiperidine, may bechosen from a list of compounds corresponding to the Z-groups listed informula (I). The amines can either be obtained commercially orsynthesized from the corresponding ketones. The protecting group P maybe chosen as stated above.

Wherein R and R* are defined in agreement with Formula I, and Prepresents a suitable protecting group, and L₁ represents a suitableleaving group.

The secondary amine C may be acylated using any isocyanate orisothiocyanate (Q₁-N═C═W) to give the corresponding ureas or thioureasD. The reaction is typically carried out by stirring the reactants,using an excess of isocyanate or isothiocyanate in an inert solvent,e.g., dichloromethane at a temperature between 0° C. and roomtemperature and under dry conditions. The amine C may also be acylatedusing any carboxylic acid halide (Q₂COX), e.g., chloride, or carboxylicanhydride ((Q₂C═O)₂O) to give amides of the general structure E. Thereaction is typically carried out using an excess of the acylating agentand a suitable base, e.g., triethylamine or diisopropylethylamine in aninert solvent, e.g., dichloromethane, at a temperature between 0° C. androom temperature and under dry conditions. As an alternative to thecarboxylic acid halides and carboxylic acid anhydrides, the amine C maybe acylated using a carboxylic acid (Q₂COOH) and a suitable couplingreagent e.g. PyBroP, DCC or EDCI. The reaction is typically carried outusing an excess of the acylating agent and the coupling reagent in aninert solvent, e.g., dichloromethane at a temperature between 0° C. androom temperature and under dry conditions. The compounds of the generalstructure (E) may be converted into the corresponding thioamides usingmethodology disclosed in Varma et al., Org. Lett. 1: 697-700 (1999);Cherkasov et al. Tetrahedron 41:2567 (1985); or Scheibye et al, Bull.Soc. Chim. Belg. 87:229 (1978).

Wherein R, Q₁, Q₂, and W are defined in agreement with formula (I), Prepresents a suitable protecting group, and X represents a halide.

The substituent T on the ring nitrogen in compounds F or G can beintroduced by a two step procedure. First, the protecting group on theurea D or the amide E is removed using well-known methods. For example,the N-Boc group is removed by treating the protected compound with 4 MHCl in dioxane or trifluoroacetic acid in dichloromethane. Second, thesecondary amines obtained from D and E can be alkylated by reductiveamination using any aldehyde (T*-CHO) or ketone (T=O). The reaction isconveniently carried out by stirring the reactants in an inert solventsuch as methanol or ethanol. As a reducing agent, solid-supportedborohydride, NaBH₄, NaCNBH₃, BH₃-pyridine, H₂/Pd—C or any relatedreagent may be used, including solid-supported reagents. The reaction istypically carried out at room temperature.

Alternatively, the compounds F and G can be synthesized from thesecondary amine obtained from D or E as described above by alkylationwith any alkylating agent (T-L₁). The leaving group L₁ is suitably ahalogen atom, e.g., bromine or iodine, or a sulfonate, e.g., tosylate ormesylate, or another leaving group favoring the reaction. The reactionis conveniently carried out by stirring the reagents under basicconditions in an inert solvent, for example diisopropylethylamine inacetonitrile, or K₂CO₃ in N,N-dimethylformamide. The reaction istypically carried out at temperatures between room temperature and 80°C.

Alternatively, the T-group can be introduced in the first step of thesynthetic sequence leading to the compounds in accordance with thepresent invention by N-alkylation of compound H with any alkylatingagent (T-L₁). The leaving group L₁ is suitably a halogen atom, e.g.,bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, oranother leaving group favoring the reaction. The reaction isconveniently carried out by stirring the reagent under basic conditionsin an inert solvent, e.g., diisopropylethylamine in acetonitrile, orK₂CO₃ in N,N-dimethylformamide. The reaction is typically carried out attemperatures between room temperature and 80° C. Alternatively theT-group can be introduced in the first step by reductive amination usingany aldehyde (T*-CHO) or ketone (T=O) and a suitably protected compoundH′, exemplified by 4-piperidone ethylene ketal. The reaction isconveniently carried out by stirring the reactants in an inert solventsuch as methanol or ethanol. As a reducing agent, solid-supportedborohydride, NaBH₄, NaCNBH₃, BH₃-pyridine, H₂/Pd—C or any relatedreagent may be used, including solid-supported reagents. The reaction istypically carried out at room temperature, but less reactive carbonylcompounds may require higher temperatures and/or the pre-formation ofthe corresponding imine under water removal before addition of thereducing agent. Removal of the protecting group gives the desiredcompound J. The secondary amine H and H′, as exemplified by 4-piperidoneand its protected derivative, may be chosen from a list of compoundscorresponding to the Z-groups listed in formula (I). The amines caneither be obtained commercially or synthesized from methodologydisclosed in Lowe et al., J. Med. Chem. 37:2831-40 (1994); and Carrollet al., J. Med. Chem. 35:2184-91 (1992).

Alternatively, compounds of the general structure J may be synthesizedstarting from K using the method disclosed in: Kuehne et al., J. Org.Chem. 56:2701 (1991); and Kuehne et al., J. Org. Chem. (1991), 56:513.

Wherein R, Q₁, Q₂, W, and T are defined in agreement with formula (I),and L₁ is a suitable leaving group.

Heterocyclylalkyl alkylating agents such as T-L₁ may be commerciallyavailable or are typically obtained by alkylation of a heterocycle witha bifunctional alkyl- linker, as shown below. The leaving groups L₁ andL₂ are suitably a halogen atom, e.g., chlorine, bromine or iodine, or asulfonate, e.g., tosylate or mesylate, or another leaving group favoringthe reaction. The reaction is conveniently carried out by stirring thereagent under basic conditions in an inert solvent, e.g.,diisopropylethylamine in acetonitrile, or K₂CO₃ inN,N-dimethylformamide. The reaction is typically carried out attemperatures between room temperature and 80° C. The alkylating agenthence obtained can be either reacted in situ in the next step with thesecondare amine (i.e. deprotected D/E, or H) or isolated from thereaction mixture before its further use. Heterocyclylalkyl alcohols suchas T*-CH₂OH or T-OH may also be converted into suitable alkylatingagents T-L, by transforming the hydroxyl into a leaving group, e.g. bytosylation, mesylation or halogenation. Alternatively, T*-CH₂OH or T-OHmay be oxidized to the corresponding aldehydes or ketones T*-CHO or T=Owith, for example, pyridinium chlorochromate, CrO₃-H₂SO₄, or via theSwern or Dess-Martin procedures, to be used in a reductive aminationstep with the secondary amines as described above.

Wherein Y, p and T are defined in agreement with formula (I), and L₁ andL₂ are suitable leaving groups.

The building blocks incorporating the aromatic groups Ar₁ and Ar₂ mayeither be obtained commercially or synthesized from methodologydisclosed in the literature. The introduction of substituents on Ar₁ andAr₂ may be performed from a suitable precursor at any appropriate stageof the preparation of the compounds.

For instance, compounds containing an alkoxy substituents may betypically prepared by Williamson ether synthesis from the correspondinghydroxyaryl derivatives.

Structures bearing an amine substituent on Ar₁ or Ar₂ may be obtainedfrom a suitable halo- or pseudohalo precursor (e.g. Br, I—, Cl—,triflate-, nonaflate-, tosylate-substituted aryl derivatives) bymetall-catalyzed amination chemistries, such as Pd— or Ni— (Hartwig,Angew. Chem. Int. Ed., 1998, 37, 2046-2067; Yang & Buchwald, J.Organometallic Chem., 1999, 576, 125-146; Hartwig in Modern AminationMethods; Ricci, Ed.; Wiley-VCH: Weinheim, Germany, 2000) or Cu-catalyzed(Buchwald et al, Org. Lett., 2002, 4, 581-584; Kwong & Buchwald, Org.Lett., 2003, 5, 793-796). Alternatively, these compounds can be obtainedfrom aniline-based precursors either by alkylation (Hickinbottom, J.Chem. Soc. 1930, 992), or by reductive amination (Emerson & Walters, J.Am. Chem. Soc., 1938, 60, 2023; Milovic et al, Synthesis, 1991, 11,1043-1045), or by dehydrative alkylation (Rice & Kohn, J. Am. Chem.Soc., 1955, 77, 4052; Brown & Reid, J. Am. Chem. Soc., 1924, 46, 1838).Additionally, compounds of this type may also be synthesized fromcorresponding boronic acids by Cu-catalyzed coupling (Antilla &Buchwald, Org. Lett., 2001, 3, 2077-2079).

The structures bearing an amide substituent on Ar₁ or Ar₂ may beobtained from a suitable halo- or pseudohalo precursor either by Pdcatalyzed (Yin & Buchwald, J. Am. Chem. Soc., 2002, 124, 6043-6048) orby Cu catalyzed (Buchwald et al, J Am. Chem. Soc., 2002, 124, 7421-7428)amidation chemistries. Alternatively, these compounds may also beobtained from the corresponding aniline precursors either by acylation(Wolf, Liebigs Ann. Chem., 1952, 576, 35; Yasukara et al, J. Chem. Soc.Perkin Trans. 1, 2000, 17, 2901-2902; Nigam & Weedon, J. Chem. Soc.,1957, 2000) or by formylation (Hirst & Cohen, J. Chem. Soc., 1895, 67,830; Olah & Kuhn, Chem. Ber. 1956, 89, 2211; Guthrie et al, Can. JChem., 1993, 71, 2109-2122).

Compounds that carry an alkylsulfanyl substituent on Ar¹ or Ar₂ beobtained from a suitable halo- or pseudohalo precursor by Pd catalyzed(Li, J. Org. Chem., 2002, 67, 3643-3650), or Cu catalyzed (Kwong &Buchwald, Org. Lett., 2002, 4, 3517-3520) thioetherification chemistry.Alternatively, these compounds may be prepared by alkylation ofcorresponding benzenethiol precursors (Vogel, J. Chem. Soc., 1948, 1809;Landini & Rocca, Synthesis, 1974, 565-566; Bun-Hoi et al, J. Org Chem.,1951, 16, 988). Alternatively, alkylarylsulfanyls may be obtained byirradiation of benzenethiols and alkenes (Screttas & Micha-Screttas, J.Org. Chem., 1978, 43, 1064-1071).

Compounds of the invention bearing an acyl group on Ar₁ or Ar₂ may beprepared from corresponding aryl iodides by Pd catalyzed (Cacchi et al,Org. Lett, 2003, 5, 289-293) acylation chemistry. Alternatively, theymay be obtained from the corresponding benzenes by Friedel-Craftschemistry (Read, J. Am. Chem. Soc., 1922, 44, 1746-1755), or by additionof aryl-Grignard reagents to nitrites (Whitmore et al, J. Am. Chem.Soc., 1947, 69, 235-237) or to acyl chlorides (Whitmore & Lester, J. Am.Chem. Soc., 1942, 64, 1247), or by either Pd-catalyzed (Gooβen & Ghosh,Angew. Chem. Int. Ed. Engl., 2001, 40, 3458-3460) or Rh-catalyzedacylation of arylboronic acids.

Compounds of the invention that bear an N-containing aromaticheterocycle on Ar₁ or Ar₂ can be obtained either by metall-catalyzedcross-couplings (Buchwald et al, Org. Lett., 2002, 2, 1403-1406;Buchwald et al, J. Am. Chem. Soc., 2001, 123, 7727-7729; Buchwald et al,J. Am. Chem. Soc., 2002, 124, 11684-11688). Alternatively, they may beaccessed from suitable precursors such as aryl hydrazines, aryl aminesor aryl nitrites according to literature procedures (e.g. Alvisi, Gazz.Chem. Ital., 1892, 22, 159; Finar, Godfrey, J. Chem. Soc., 1954, 2293;Muri et al, Synth. Commun., 1998, 28, 1299-1321; Artico et al, Europ. J.Med. Chem. Chim. Ther., 1992, 27, 219-228; Biagi et al., Farmaco Ed.Sci. 1988, 43, 597-612; Stefancich et al, Farmaco Ed. Sci., 1984, 39,752-764).

In general, during any of the processes for preparation of the compoundsof the present invention, it may be necessary and/or desirable toprotect sensitive or reactive groups on any of the molecules concerned.This may be achieved by means of conventional protecting groups, such asthose described in Protective Groups in Organic Chemistry (ed. J. F. W.McOmie, Plenum Press, 1973); and Greene & Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991. The protecting groups may beremoved at a convenient subsequent stage using methods known from theart.

EXAMPLES

The examples below are non-limiting and are only illustrative of some ofthe embodiments of the present invention.

Chemical Synthesis

General procedures. ¹H NMR spectra were recorded at 400 MHz on a VarianMercury-VX400 MHz spectrometer and chemical shifts are given in 6-values[ppm] referenced to the residual solvent peak chloroform (CDCl₃) at 7.26and methanol (CD₃OD) at 3.31 ppm. Coupling constants, J, are reported inHertz. Unless otherwise stated, the NMR spectra of the compounds aredescribed for their free amine form. Due to the presence of rotamers,two sets of signals are generally observed and rotamer ratios arereported. Where the corresponding signals for each of the two rotamerscould unmistakably be identified, they are reported together [e.g.4.66-4.58 and 3.76-3.68 (2m, 1H)]. Acidic ion-exchange solid phaseextraction (SPE) cartridges were MEGA BE-SCX from Varian.

Materials and solvents were of the highest grade available fromcommercial sources and were used without further purification.

HPLC/LCMS Method. The analysis was performed on a combinedprep/analytical Waters/Micromass system consisting of a ZMD singlequadropole mass spectrometer equipped with electrospray ionizationinterface. The HPLC system consisted of a Waters 600 gradient pump withon-line degassing, a 2700 sample manager and a 996 PDA detector.Separation was performed on an X-Terra MS C18, 5 μm 4.6×50 mm column.Buffer A: 10 mM ammoniumacetate in water, buffer B: 10 mM ammoniuacetatein acetonitrile/water 95/5. A gradient was run from 30% B to 100% B in 7min, hold at 100% B for 1 min and re-equilibrated for 5.5 min. Thesystem was operated at 1 ml/min.

Preparation of hydrochloride salts. Typically, the tertiary amines weredissolved in dichloromethane, treated with an excess of 1M HCl indiethylether and precipitated from n-heptane. The solvents were removedin vacuo and after drying, the hydrochloride salts were obtained ascolourless solids.

Preparation of oxalate or tartrate salts. Typically, the tertiary amineswere dissolved in methanol, treated with 1 eq. of the appropriate acid,the solvent removed and the salt redissolved in dichloromethane andprecipitated from n-heptane. The solvents were removed in vacuoaffording the salts as colourless solids.

Preparation of Phenylacetyl Chloride Derivatives

The phenylacetic acid derivative (15 mmol) was dissolved indichloromethane (100 mL), and oxalylchloride (45 mmol) was added slowly.The reaction mixture was stirred for 4 hours and then evaporated todryness. The product was obtained as a colourless oil and usedimmediately after preparation in the acylation step.

4-Isobutoxyphenylacetic acid (128NLS28)

Methyl 4-hydroxyphenyl acetate (14.6 g, 0.0885 mol) was dissolved in DMF(200 mL), potassium carbonate (31.0 g, 0.224 mmol) added and the mixturewas stirred for 1 h at rt. 1-Bromo-2-methylpropane (19.2 mL, 0.177 mol)was added and the mixture was heated at 80° C. for 3 days under vigorousstirring. The mixture was cooled to rt, filtered, the solvent removedand the residue partitioned between 1.5M NaOH and ethyl acetate. Theorganic layer was evaporated, the residue dissolved in methanol (100 mL)and water (100 mL), KOH (10 g, 0.178 mol) added and the mixture stirredovernight at rt. The methanol was removed by evaporation, the mixtureextracted with dichloromethane. The organic layer was discarded, theaqueous layer acidified with 4M HCl to pH2-3 and extracted twice withdichloromethane. The combined organic layers were dried over Na₂SO₄,filtered and evaporated to give the title compound (16.9 g, 92%) as acolourless solid.

4-Propoxyphenylacetic acid (98AF77-66)

Prepared as described for 128NLS28 using propylbromide as the alkylatingagent.

4-Isopropoxyphenylacetic acid (130AF24-163)

Prepared as described for 128NLS28 using isopropylbromide as thealkylating agent.

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isobutoxybenzyl)carbamidehydrochloride (80MBT86-2C)

4-Piperidone hydrochloride monohydrate (4.0 g, 26.0 mmol) was dissolvedin dichloromethane (130 mL). After addition of triethylamine (8.66 g,85.8 mmol), the mixture was stirred for 10 min and then cooled to 0° C.Trifluoroacetic anhydride (12.0 g, 57.2 mmol) was added dropwise understirring. After 2 h at room temperature, the reaction was stopped byaddition of water (100 mL), and the aqueous phase was extracted withdichloromethane (2×100 mL). The combined organic phases were dried overNa₂SO₄, filtered and concentrated to give1-(trifluoroacetyl)-4-piperidone (5.07 g, 100%).

4-Fluorobenzylamine (3.14 g, 25.9 mmol) was dissolved in methanol (150mL). 1-(trifluoroacetyl)-4-piperidone (5.07 g, 25.9 mmol) was added, andthe pH was adjusted to ˜5 with acetic acid. The reaction mixture wasstirred for 5 min and NaBH₃CN (2.46 g, 38.9 mmol) was added slowly understirring. After 20 h at room temperature the reaction was concentrated.2 M NaOH (100 mL) was added and the aqueous phase was extracted withdichloromethane (2×100 mL). The combined organic phases were dried overNa₂SO₄, filtered and concentrated to giveN-(4-fluorobenzyl)-1-(trifluoroacetyl)piperidin-4-amine (50ELH85, 2.91g, 37%).

4-isobutoxyphenylacetic acid (7.6 g, 36.5 mmol) was dissolved in THF (50mL). Proton Sponge™ (8.2 g, 38 mmol) was added, and the mixture wasstirred for 15 min. Diphenylphosphoryl azide (10.6 g, 38 mmol) was addeddropwise and the mixture was heated to reflux for 4 h. The mixture wascooled to room temperature and placed in the freezer at −18° C. for 20h. The resulting white precipitate was vigorously stirred with diethylether (250 mL) for 15 min and filtered. The filtrate was evaporated togive crude 4-isobutoxybenzyl isocyanate (1.97 g, 9.6 mmol), which wasdissolved in dichloromethane (50 mL) and added to a solution of 50ELH85(2.91 g, 9.6 mmol) in dichloromethane (50 mL). The reaction mixture wasstirred for 20 h and concentrated. The crude product was purified byflash chromatography (0-5% methanol in dichloromethane) to giveN-(4-fluorobenzyl)-N-[1-(trifluoroacetyl)piperidin-4-yl]-N′-(4-isobutyloxybenzyl)carbamide(76ELH17, 3.90 g, 91%).

The compound 76ELH17 (3.90 g, 8.7 mmol) was dissolved in methanol (12ml) and added to a 2 M solution of potassium carbonate in methanol (100mL) under stirring. After 4 h the methanol was evaporated, and theaqueous phase was extracted with dichloromethane (2×100 mL). Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated to give a semi-pure solid (2.95 g), which was purified byflash chromatography (10% methanol in dichloromethane with 1%triethylamine) to giveN-(4-fluorobenzyl)-N-(piperidin-4-yl)-N′-(4-isobutyloxybenzyl)carbamide(76ELH 18, 1.40 g, 39%) as a colourless solid. LCMS m/z 414 [M+H]⁺.¹H-NMR (CDCl₃): δ 7.21-6.75 (m, 8H), 4.47-4.42 (m, 1H), 4.39 (t, J=5 Hz,1H), 4.35 (s, 2H), 4.27 (d, J=5 Hz, 2H), 3.68 (d, J=6 Hz, 2H), 3.13-3.06(m, 2H), 2.74-2.66 (m, 2H), 2.11-1.99 (m, 1H), 1.78-1.71 (m, 3H),1.58-1.46 (m, 2H), 1.00 (d, J=6 Hz, 6H).

The compound 76ELH18 (200 mg, 0.484 mmol) was dissolved in acetonitrile(20 mL). Potassium carbonate (74 mg, 0.553 mmol) and sodium iodide (80mg, 0.553 mmol) was added followed by 2-(2-bromoethyl)-1,3-dioxolane(100 mg, 0.553 mmol). The reaction mixture was heated to reflux for 20h. The mixture was concentrated, water (50 mL) was added, and theaqueous phase was extracted with dichloromethane (2×50 mL). The combinedorganic phases were dried over Na₂SO₄, filtered and evaporated. Theresulting oil was purified twice by flash chromatography (5% methanol indichloromethane) to give a colourless oil (50 mg, 20%). R_(f)=0.70(MeOH/CH₂Cl₂ 1:9). LCMS m/z 514 [M+H]⁺. ¹H-NMR (CDCl₃): δ 7.21-6.75 (m,8H), 4.94 (t, J=4.5 Hz, 1H), 4.73-4.62 (m, 1H), 4.58 (t, J=5.5 Hz, 1H),4.41 (s, 2H), 4.26 (d, J=5.5 Hz, 2H), 4.00-3.80 (m, 4H), 3.68 (d, J=6.0Hz, 2H), 3.43-3.35 (m, 2H), 2.94-2.87 (m, 2H), 2.68-2.57 (m, 2H),2.45-2.32 (m, 2H), 2.20-2.13 (m, 2H), 2.10-2.00 (m, 1H), 1.88-1.81 (m,2H), 1.00 (d, J=6.0 Hz, 6H). HPLC t_(R)=8.1 min.

The collected compound was converted into its hydrochloride salt, whichwas obtained as a colourless solid (80MBT86-2C).

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-hydroxy-2-methylpropoxy)phenyl]acetamide,tartrate (106MBT54D)

Methyl (4-hydroxyphenyl)acetate (500 mg, 3.0 mmol) was dissolved in DMF(3 mL). K₂CO₃ (829 mg, 6.0 mmol) was added followed by isobutylene oxide(800 μL, 9.0 mmol). The mixture was heated to 150° C. by microwaveirradiation for 30 min and concentrated. The residue was dissolved in a1:1 mixture of methanol and water (20 mL). NaOH (1 g) was added and themixture was stirred for 30 min. Methanol was removed by rotaryevaporation. The aqueous phase was acidified by 4 M HCl and extractedwith dichloromethane (2×50 mL). The combined organic phases wereextracted with 2 M NaOH (2×50 mL). The combined aqueous phases weresubsequently acidified by 4 M HCl and extracted with dichloromethane(2×50 mL). The combined organic phases were dried over Na₂SO₄, filteredand evaporated to afford [4-(2-hydroxy-2-methylpropoxy)phenyl]aceticacid (106MBT52-D, 470 mg, 70%) as a colourless solid. ¹H-NMR (CDCl₃): δ7.19 (m, 2H), 6.88 (m, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 1.34 (s. 6H).

The acid 106MBT52-D (150 mg, 0.67 mmol) was dissolved in dichloromethane(10 mL).N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine(118AF52-95, 180 mg, 0.56 mmol) was added followed by triethylamine (235μL, 0.84 mmol). Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBroP, 392 mg, 0.84 mmol) was added, and the mixture was stirred atroom temperature for 2 h. The mixture was concentrated and passed onto aprewashed (methanol) ion exchange column (0.88 mmol/g, 1 g). The columnwas washed with methanol (8×4 mL) and the remaining product was elutedoff the column with 10% NH₄OH in methanol (2×4 mL) and evaporated. Theresulting oil was dissolved in dichloromethane (20 mL) and washed withsaturated aqueous NaHCO₃ (5×20 mL). The organic phase was dried overNa₂SO₄, filtered and evaporated. The resulting oil was purified by flashchromatography (0-5% methanol in dichloromethane) to give a colourlessoil (110 mg, 31%). R_(f)=0.64 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 529 [M+H]⁺.¹H-NMR (CDCl₃, rotamers 0.4:0.6): δ 7.25-6.82 (m, 8H), 4.64-4,48 (m,2.4H), 4.44 (s, 1.2H), 4.10-4.03 (m, 2H), 3.79-3.67 (m, 5.2H), 3.50 (s,1.2H), 2.90-2.81 (m, 2H), 2.42-3.95 (m, 2H), 2.12-1.98 (m, 2.2H),1.87-1.79 (m, 0.8H), 1.76-1.48 (m, 5.2H), 1.36-1.27 (m, 7.8H). HPLCt_(R)=6.1 min.

The collected compound was converted into its tartrate salt, which wasobtained as a colourless solid (106MBT54-D).

N-(4-Fluorobenyzl)-N-(piperidin-4-yl)-2-(4-isobutoxyphenyl-acetamide(103NLS56)

To a solution of the amine 118AF93-51 (10.37 g, 30.3 mmol) andtriethylamine (9.36 mL, 60.6 mmol) in dichloromethane (200 mL) asolution of 4-isobutoxyphenylacetyl chloride 128NLS28 (8.93 g, 39.4mmol) in dichloromethane (100 mL) is added dropwise at 0° C. Thesolution is stirred at rt for 3 h, then water is added and the mixturewashed with sat. aq. NaHCO3. The organic layer was washed with 5% HCl,water and brine, dried over sodium sulfate, filtered and evaporated invacuo. The residue was purified by silica gel column chromatographyeluting with a stepwise gradient of 0-50% ethyl acetate in n-heptane,affordingN-(4-Fluorobenyzl)-N-[1-(benzyloxycarbonyl)piperidin-4-yl]-2-(4-isobutoxyphenyl)acetamideas a colourless oil.

This compound was dissolved in abs. ethanol (200 mL) and hydrogenatedovernight at rt using Pd/C (10%, 1 g) as a catalyst. The mixture wasfiltered over Celite, the solvent removed and the residue dried in vacuoto give a colourless oil (7.02 g, 58% over both steps). This compoundwas used without further purification. LCMS m/z 399 [M+H]⁺.

HPLC t_(R)=8.8 min.

N-{1-[3-(3,5-Dimethylpiperidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamidedihydrochloride (103NLS45-B)

To 3,5-dimethylpiperidine (43 μL, 0.33 mmol) in DMF (1 mL) was addedpotassium carbonate (132 mg, 1.0 mmol), followed by1-chloro-3-iodopropane (32 μmol, 0.30 mmol) and the mixture stirred at50° C. for 2 h. After cooling to rt, a solution of 103NLS56 (100 mg,0.25 mmol) in DMF (0.5 mL) was added, followed by sodium iodide (45 mg,0.30 mmol). The mixture was shaken for 20 h at 60° C., filtered,evaporated to dryness and purified by silica gel column chromatography,eluting with a stepwise gradient of 0-10% methanol in dichloromethane.The residue was further purified by passage over a reversed phase C₁₈SPE cartridge, giving the desired compound (35 mg, 25%), which wasconverted into its dihydrochloride salt.

R_(f)=0.61 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 552 [M+H]⁺. HPLC t_(R)=8.7 min.

1-[3-(4-{(4-Fluorobenzyl)-[2-(4-isobutoxyphenyl)acetyl]amino}piperidin-1-yl)propyl]piperidine-4-carboxylicacid methyl ester, dihydrochloride (103NLS45E)

Prepared following the same method as described for 103NLS45-B, usingpiperidine-4-carboxylic acid methyl ester (44 μL, 0.33 mmol). Yield: 7mg, 5%.

LCMS m/z 582 [M+H]⁺. HPLC t_(R)=7.8 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1-methylpyrrolidin-2-yl)ethyl]piperidin-4-yl}acetamide,dioxalate (103NLS63-G).

To a solution of the amine 103NLS56 (15 mg, 0.038 mmol) in DMF (0.3 mL)was added a solution of 2-(2-chloroethyl)-1-methylpyrrolidinehydrochloride (8.4 mg, 0.045 mmol) in DMF (0.1 mL), followed by caesiumcarbonate (50 mg, 0.15 mmol) and sodium iodide (6.8 mg, 0.045 mmol). Themixture was stirred overnight at 60° C., partitioned betweendichloromethane and sat. aq. NaHCO₃ solution. The organic layer wasdried over sodium sulfate, filtered and evaporated. The residue waspurified by preparative reversed phase (C₁₈) HPLC and the obtainedcompound (10.5 mg, 54%) converted into its dioxalate salt.

LCMS m/z 510 [M+H]⁺. HPLC t_(R)=8.1 min.

N-{1-[3-(2,6-Dimethylmorpholin-4-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,dioxalate (103NLS69-A)

To a solution of 2,6-dimethylmorpholine (6.1 μL, 49 μmol) in DMF (0.3mL) 1-chloro-3-iodopropane (4.9 μL, 45 μmol) in DMF (0.05 mL) was added,followed by caesium carbonate (50 mg, 0.15 mmol). The mixture was shakenat 50° C. for 3 h. After cooling to rt, the piperidine derivative103NLS56 (15 mg, 38 μmol) in DMF (0.1 mL) and sodium iodide (6.8 mg, 45μmol) were added and stirring maintained overnight at 60° C. The mixturewas partitioned between dichloromethane and sat. aq. NaHCO₃ solution.The organic layer was dried over sodium sulfate, filtered andevaporated. The residue was purified by preparative reversed phase (C₁₈)HPLC and the obtained compound (6.3 mg, 30%) converted into itsdioxolate salt.

LCMS m/z 554 [M+H]⁺. HPLC t_(R)=8.7 min.

N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxypiperidin-1-yl)propyl]piperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide,dioxalate (103NLS69-B)

Prepared following the same method as described for 103NLS69-A, using3-hydroxypiperidine hydrochloride (6.8 mg, 49 μmol). Yield: 7.9 mg, 30%.LCMS m/z 540 [M+H]⁺. HPLC t_(R)=8.1 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-methylpiperidin-1-yl)propyl]piperidin-4-yl}acetamide,dioxalate (103NLS69-C)

Prepared following the same method as described for 103NLS69-A, using2-methylpiperidine (5.8 μL, 49 μmol). Yield: 5.2 mg, 26%. LCMS m/z 538[M+H]⁺. HPLC t_(R)=8.7 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(3-pyrrolidin-1-yl-propyl)piperidin-4-yl]acetamidedioxalate (103NLS69-D

Prepared following the same method as described for 103NLS69-A, usingpyrrolidine (5.0 μL, 49 μmol). Yield: 4.6 mg, 24%. LCMS m/z 510 [M+H]⁺.HPLC t_(R)=8.4 min.

N-{1-[3-(2,5-Dimethylpyrrolidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,dioxalate (103NLS69-E)

Prepared following the same method as described for 103NLS69-A, using2,5-dimethylpyrrolidine (6.0 μL, 49 μmol). Yield: 3.4 mg, 17%. LCMS m/z538 [M+H]⁺. HPLC t_(R)=8.7 min.

N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxymethylpiperidin-1-yl)propyl]piperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide,dioxalate (103NLS69-F)

Prepared following the same method as described for 103NLS69-A, using3-hydroxymethylpiperidine (5.5 μL, 49 μmol). Yield: 5.5 mg, 26%. LCMSm/z 554 [M+H]⁺. HPLC t_(R)=8.0 min.

(4S)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one (103NLS94)

Sodium hydride (60% suspension in oil, 288 mg, 7.2 mmol) was added to asolution of (S)-4-isopropyl-2-oxazolidinone (775 mg, 6.0 mmol) in drytetrahydrofuran (50 mL) under argon atmosphere. The suspension wasstirred for 15 min at rt, then 1-bromo-3-chloropropane (1.18 mL, 12.0mmol) was added dropwise over 30 min. The mixture was refluxedovernight, filtered and the filtrate evaporated in vacuo. Purificationof the residue by silica gel column chromatography, eluting with astepwise gradient of 0-4% methanol in dichloromethane afforded(4S)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one (824 mg, 67 %) asa colourless oil.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate (11 7NLS01)

To a solution of 103NLS56 (207 mg, 0.52 mmol) potassium carbonate (215mg, 1.56 mmol) was added, followed by the alkylating agent 103NLS94 (127mg, 0.62 mmol) and sodium iodide (93 mg, 0.62 mmol). The mixture wasstirred at 65° C. overnight, the solvent removed and the residuepartitioned between ethyl acetate and water. The organic layer was driedover Na₂SO₄, filtered and evaporated. The residue was purified by silicagel column chromatography, eluting with a stepwise gradient of 0-4%methanol in dichloromethane. Further purification of the compound wasperformed by passage over an acidic ion exchange SPE cartridge,affording the desired compound (209 mg, 71%) as a colourless oil, whichwas converted into its oxalate salt.

R_(f)=0.35 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 568 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.21-6.80 (m, 8H, Ar—H), 4.60-4.53 (m, 0.6H, pip-H),4.49 and 4.43 (2s, 2H, benzyl-H), 4.19-4.14 (m, 1H, oxa-CH₂), 4.06-4.01(m, 1H, oxa-CH₂), 3.77-3.67 (m, 4.2H, pip-H, oxa-NCH, CH_(2OiBu),benzyl-H), 3.53-3.46 (m, 2.2H, benzyl-H, OCONCH₂), 2.98-2.85 (m, 3H,pip-H, OCONCH₂), 2.39-2.25 (m, 2H, NCH₂), 2.10-2.00 (m, 3.2H, CH(CH₃)₂,pip-H, CH_(OiBu)), 1.85-1.50 (m, 6H, pip-H, NCH₂CH₂), 1.29 (m, 0.8H,pip-H), 1.01-0.99 (m, 6H, CH_(3OiBu)), 0.89-0.83 (m, 6H, CH(CH₃)₂). HPLCt_(R)=8.9 min.

N-[2-(4-Fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate (117NLS03-A)

Prepared following the same method as described for 117NLSO1 usingN-[2-(4-fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)-N-(piperidin-4-yl)acetamide(111 mg, 0.27 mmol, prepared by the procedure described for 103NLS56).Yield: 90 mg, 57%.

R_(f)=0.30 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 582 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.18-6.80 (m, 8H, Ar—H), 4.40-4.35 (m, 0.4H, pip-H),4.20-4.15 (m, 1H, oxa-CH₂), 4.05-4.01 (m, 1H, oxa-CH₂), 3.75-3.46 (m,6.6H, pip-H, oxa-NCH, CH_(2OiBu), benzyl-H, OCONCH₂), 3.36 (m, 2H,ArCH₂CH₂N), 3.02-2.84 (m, 3H, pip-H, OCONCH₂), 2.81-2.75 (m, 2H, ArCH₂),2.37-2.25 (m, 2H, NCH₂), 2.09-1.98 (m, 2.8H, CH(CH₃)₂, pip-H,CH_(OiBu)), 1.85-1.62 (m, 6H, pip-H, NCH₂CH₂), 1.31 (m, 1.2H, pip-H),1.00-0.97 (m, 6H, CH_(3OiBu)), 0.89-0.84 (m, 6H, CH(CH₃)₂). HPLCt_(R)=9.1 min.

N-[2-(4-Fluorophenyl)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide,oxalate (117NLS03-B)

Prepared following the same method as described for 117NLS01 usingN-[2-(4-fluorophenyl)ethyl]-N-(piperidin-4-yl)-2-(4-propoxyphenyl)acetamide(108 mg, 0.27 mmol, prepared by the procedure described for 103NLS56).Yield: 76 mg, 50%.

R_(f)=0.33 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 568 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.17-6.81 (m, 8H, Ar—H), 4.40-4.35 (m, 0.4H, pip-H),4.20-4.15 (m, 1H, oxa-CH₂), 4.05-4.01 (m, 1H, oxa-CH₂), 3.90-3.85 (m,2H, OCH_(2OPr)), 3.72-3.48 (m, 4.6H, pip-H, oxa-NCH, benzyl-H, OCONCH₂),3.36-3.30 (m, 2H, ArCH₂CH₂N), 2.99-2.86 (m, 3H, pip-H, OCONCH₂),2.80-2.74 (m, 2H, ArCH₂), 2.38-2.26 (m, 2H, NCH₂), 2.11-2.03 (m, 1.8H,CH(CH₃)₂, pip-H), 1.87-1.64 (m, 8H, pip-H, CH_(2OPr), NCH₂CH₂), 1.31 (m,1.2H, pip-H), 1.03-0.98 (m, 3H, CH_(3OPr)), 0.88-0.83 (m, 6H, CH(CH₃)₂).HPLC t_(R)=8.5 min.

N-(4-Fluorobenzyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide,oxalate (117NLS03-C)

Prepared following the same method as described for 117NLSO1 usingN-(4-fluorobenzyl)-N-(piperidin-4-yl)-2-(4-propoxyphenyl)acetamide (104mg, 0.27 mmol, prepared by the procedure described for 103NLS56). Yield:120 mg, 80%.

R_(f)=0.36 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 554 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.19-6.78 (m, 8H, Ar—H), 4.57-4.48 (m, 0.6H, pip-H),4.48 and 4.42 (2s, 2H, benzyl-H), 4.18-4.12 (m, 1H, oxa-CH₂), 4.04-4.00(m, 1H, oxa-CH₂), 3.91-3.85 (m, 2H, OCH_(2OPr)), 3.75-3.66 (m, 2.2H,pip-H, oxa-NCH, benzyl-H), 3.49-3.43 (m, 2.2H, benzyl-H, OCONCH₂),2.98-2.80 (m, 3H, pip-H, OCONCH₂), 2.33-2.25 (m, 2H, NCH₂), 2.05-1.50(m, 10.2H, CH(CH₃)₂, NCH₂CH₂, pip-H, CH_(2OPr)), 1.27 (m, 0.8H, pip-H),1.18-0.98 (m, 3H, CH_(3OPr)), 0.87-0.81 (m, 6H, CH(CH₃)₂). HPLCt_(R)=8.3 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzal)-2-(4-isobutoxyphenyl)acetamide,oxalate (103NLS63-F)

Prepared following the same method as described for 117NLS01 using and103NLS56 (262 mg, 0.657 mmol) and 2-(2-bromoethyl)-1,3-dioxane as thealkylating agent. No sodium iodide was required. Yield: 152 mg, 45%.

R_(f)=0.35 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 513 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.26-6.80 (m, 8H, Ar—H), 4.63-4.39 (m, 3.6H, pip-H,dioxane-H, benzyl-H), 4.09-4.01 (m, 2H, dioxane-H), 3.78-3.64 (m, 5.2H,pip-H, dioxane-H, CH_(2OiBu), benzyl-H), 3.50 (s, 1.2H, benzyl-H),2.92-2.79 (m, 2H, pip-H), 2.43-2.34 (m, 2H, NCH₂), 2.10-1.96 (m, 3.2H,dioxane-H, pip-H, CH_(OiBu)), 1.88-1.48 (m, 6H, pip-H, NCH₂CH₂),1.35-1.24 (m, 1.8H, dioxane-H, pip-H), 1.01 (m, 6H, CH_(3OiBu)). HPLCt_(R)=8.8 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)acetamide,oxalate (117NLS03-D)

Prepared following the same method as described for 117NLS03-A using2-(2-bromoethyl)-1,3-dioxane as the alkylating agent. No sodium iodidewas required. Yield: 99 mg, 70%.

R_(f)=0.35 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 527 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.7:0.3) δ 7.18-6.80 (m, 8H, Ar—H), 4.58-4.54 (m, 1H,dioxane-H), 4.48-4.41 (m, 0.3H, pip-H), 4.10-4.06 (m, 2H, dioxane-H),3.77-3.66 (m, 5.4H, dioxane-H, benzyl-H, CH_(2OiBu)), 3.64-3.52 (m,1.3H, benzyl-H, pip-H), 3.37-3.32 (m, 2H, CH₂NCO), 2.99 and 2.89 (2m,2H, pip-H), 2.82-2.76 (m, 2H, ArCH₂), 2.49-2.39 (m, 2H, NCH₂), 2.12-2.00(m, 2.6H, dioxane-H, pip-H, CH_(OiBu)), 1.88-1.67 (m, 6H, pip-H,CH_(2OiBu), NCH₂CH₂), 1.35-1.31 (m, 2.4H, dioxane-H, pip-H), 1.00 (t,6H, J=6.6, CH_(3OiBu)). HPLC t_(R)=8.8 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-2-(4-propoxyphenyl)acetamide,oxalate (117NLS03-E)

Prepared following the same method as described for 117NLS03-B using2-(2-bromoethyl)-1,3-dioxane as the alkylating agent. No sodium iodidewas required. Yield: 90 mg, 65%.

R_(f)=0.23 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 513 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.7:0.3) δ 7.21-6.81 (m, 8H, Ar—H), 4.58-4.54 (m, 1H,dioxane-H), 4.48-4.42 (m 0.3H, pip-H), 4.10-4.06 (m, 2H, dioxane-H),3.91-3.86 (m, 2H, CH_(2OPr)), 3.77-3.69 (m, 3.4H, dioxane-H, benzyl-H),3.63-3.56 (m, 1.3H, benzyl-H, pip-H), 3.38-3.31 (m, 2H, CH₂NCO), 2.99and 2.89 (2m, 2H, pip-H), 2.82-2.76 (m, 2H, ArCH₂), 2.49-2.39 (m, 2H,NCH₂), 2.12-2.00 (m, 1.6H, dioxane-H, pip-H), 1.87-1.65 (m, 8H, pip-H,CH_(2OPr), NCH₂CH₂), 1.35-1.31 (m, 2.4H, dioxane-H, pip-H), 1.05-1.00(m, 3H, CH_(3OPr)). HPLC t_(R)=8.0 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide,tartrate (117NLS03-F)

Prepared following the same method as described for 117NLS03-C using2-(2-bromoethyl)-1,3-dioxane as the alkylating agent. No sodium iodidewas required. Yield: 107 mg, 79%.

R_(f)=0.41 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 499 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.20-6.80 (m, 8H, Ar—H), 4.62-4.56 (m, 0.6H, pip-H),4.54-4.51 (m, 1H, dioxane-H), 4.49 and 4.43 (2s, 2H, benzyl-H),4.08-4.04 (m, 2H, dioxane-H), 3.92-3.87 (m, 2H, OCH_(2OPr)), 3.76-3.68(m, 3.2H, pip-H, dioxane-H, benzyl-H), 3.50 (s, 1.2H, benzyl-H),2.90-2.83 (m, 2H, pip-H), 2.43-2.36 (m, 2H, NCH₂), 2.10-1.98 (m, 2.2H,dioxane-H, pip-H,), 1.86-1.51 (m, 8H, pip-H, CH_(2OPr), NCH₂CH₂),1.32-1.27 (m, 1.8H, dioxane-H, pip-H), 1.05-0.99 (m, 3H, CH₃). HPLCt_(R)=7.6 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isobutoxybenzyl)carbamide,tartrate (117NLS25)

Prepared following the same method as described for 117NLSO1 using2-(2-bromoethyl)-1,3-dioxane (24 μL, 0.18 mmol) as the alkylating agentandN-(4-fluorobenzyl)-N′-(4-isobutoxybenzyl)-N-(piperidin-4-yl)carbamide(76ELH18, 50 mg, 0.12 mmol). No sodium iodide was required. Yield: 38mg, 60%.

R_(f)=0.32 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 528 [M+H]⁺. ¹H-NMR (CDCl₃) δ7.18-6.74 (m, 8H, Ar—H), 4.53 (t, 1H, J=5.1, dioxane-H), 4.46 (t, 1H,J=5.3, NH), 4.33-4.25 (m, 5H, pip-H, benzyl-H), 4.08-4.04 (m, 2H,dioxane-H), 3.75-3.68 (m, 2H, dioxane-H), 3.66 (d, 2H, J=6.6,CH_(2OiBu)), 2.93-2.88 (m, 2H, pip-H), 2.43-2.39 (m, 2H, NCH₂),2.09-1.98 (m, 4H, CH_(OiBu), dioxane-H, pip-H), 1.77-1.56 (m, 6H, pip-H,NCH₂CH₂), 1.32-1.28 (m, 1H, dioxane-H), 0.99 (d, 6H, J=6.6, CH_(3OiBu)).HPLC t_(R)=8.7 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate (117NLS87-A)

To a solution of 118AF52-95 (300 mg, 0.93 mmol) and triethylamine (0.52mL, 3.72 mmol) in dry THF (10 mL) at 0° C. a solution of4-fluorophenylacetyl chloride (0.19 mL, 1.39 mmol) in THF (5 mL) wasadded dropwise and stirring was continued at rt for 3 h. The reactionmixture was filtered and the filtrate evaporated to dryness. The residuewas partitioned between ethyl acetate and 1M NaOH, the organic layerwashed with brine, dried over Na₂SO₄, filtered and evaporated.Purification by silica gel column chromatography, eluting with astepwise gradient of 0-8% methanol in dichloromethane, followed bypurification of the compound by passage over an acidic ion exchange SPEcartridge, afforded the desired compound (131 mg, 31%), which wasconverted to its tartrate form as described above.

R_(f)=0.39 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 459 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.25-6.88 (m, 8H, Ar—H), 4.58-4.52 (m, 0.6H, pip-H),4.50 (t, 1H, J=5.1, dioxane-H), 4.48 and 4.44 (2s, 2H, benzyl-H),4.06-4.02 (m, 2H, dioxane-H), 3.78 and 3.50 (2s, 2H, benzyl-H),3.72-3.64 (m, 2.4H, pip-H, dioxane-H), 2.84 (m, 2H, pip-H), 2.40-2.35(m, 2H, NCH₂), 2.07-1.99 (m, 2.2H, dioxane-H, pip-H), 1.85-1.50 (m, 6H,pip-H, NCH₂CH₂), 1.30-1.25 (m, 1.8H, dioxane-H, pip-H). HPLC t_(R)=6.9min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-p-tolylacetamide,tartrate (117NLS87-B)

Prepared following the same method as described for 117NLS87-A using4-methylphenylacetyl chloride and 118AF52-95 (300 mg, 0.93 mmol). Yield:119 mg, 28%.

R_(f)=0.43 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 455 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.5:0.5) δ 7.17-6.87 (m, 8H, Ar—H), 4.60-4.53 (m, 0.5H, pip-H),4.50 (t, 1H, J=5.1, dioxane-H), 4.48 and 4.41 (2s, 2H, benzyl-H),4.05-4.01 (m, 2H, dioxane-H), 3.77-3.66 (m, 3.5H, pip-H, benzyl-H,dioxane-H), 3.50 (s, 1H, benzyl-H), 2.87-2.80 (m, 2H, pip-H), 2.40-2.34(m, 2H, NCH₂), 2.30 and 2.28 (2s, 3H, CH₃), 2.07-1.95 (m, 2H, dioxane-H,pip-H), 1.83-1.50 (m, 6H, pip-H, NCH₂CH₂), 1.29-1.25 (m, 2H, dioxane-H,pip-H). HPLC t_(R)=7.7 min.

2-Benzofuran-5-yl-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate (128NLS22-A)

Benzofuran-5-yl-acetic acid was prepared adapting a procedure by Dunn etal. (J. Med. Chem., 1986, 29, 2326) and converted into the correspondingacetyl chloride by treatment with oxalylchloride. The title compound wasprepared from 118AF52-95 (58 mg, 0.18 mmol) following the same method asdescribed for 117NLS87-A. Yield: 27 mg, 43%.

R_(f)=0.52 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 481 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.64-6.68 (m, 9H, Ar—H), 4.62-4.54 (m, 0.6H, pip-H)4.53-4.44 (m, 3H, dioxane-H, benzyl-H), 4.07-4.03 (m, 2H, dioxane-H),3.82-3.61 (m, 3.2H, pip-H, benzyl-H, dioxane-H), 3.45 (s, 1.2H,benzyl-H), 2.91-2.80 (m, 2H, pip-H), 2.44-2.35 (m, 2H, NCH₂), 2.08-1.98(m, 2.2H, dioxane-H, pip-H), 1.85-1.56 (m, 6H, pip-H, NCH₂CH₂),1.32-1.27 (m, 1.8H, dioxane-H, pip-H). HPLC t_(R)=6.6 min.

2-(2,3-Dihydrobenzofuran-5-yl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate (128NLS22-B)

The compound (2,3-Dihydrobenzofuran-5-yl)acetic acid was preparedadapting a procedure by Dunn et al. (J. Med. Chem., 1986, 29, 2326) andconverted into the corresponding acetyl chloride by treatment withoxalylchloride. The title compound was prepared from 118AF52-95 (58 mg,0.18 mmol) following the same method as described for 117NLS87-A. Yield:27 mg, 31%.

R_(f)=0.50 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 483 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.10-6.60 (m, 7H, Ar—H), 4.55-4.40 (m, 5.6H, pip-H,dioxane-H. benzyl-H, ArOCH₂), 4.01-3.97 (m, 2H, dioxane-H), 3.72-3.62(m, 3.2H, pip-H, benzyl-H, dioxane-H), 3.41 (s, 1.2H, benzyl-H),3.14-3.06 (m, 2H, OCH₂CH₂), 2.80 (m, 2H, pip-H), 2.35-2.30 (m, 2H,NCH₂), 1.99-1.93 (m, 2.2H, dioxane-H, pip-H), 1.80-1.44 (m, 6H, pip-H,NCH₂CH₂), 1.27-1.22 (m, 1.8H, dioxane-H, pip-H). HPLC t_(R)=6.9 min.

N-{1-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzal)-2-(4-isobutoxyphenyl)acetamide,tartrate (11 7NLS37)

1-(2′,2′-Dimethyl-1′,3′-dioxolan-4′-yl)ethanol was prepared according toliterature procedures (Carman R. M et al., Aust. J. Chem., 1998, 51,955) and oxidized to the aldehyde by treatment with pyridiniumchlorochromate. The crude aldehyde (80 mg, 0.55 mmol) was added to asolution of 103NLS56 (184 mg, 0.46 mmol) in methanol (5 mL). Acetic acid(0.05 mL) was added, followed by sodium cyanoborohydride (58 mg, 0.92mmol) and the mixture stirred overnight at rt. The solvent was removedand the residue partitioned between dichloromethane and 1M NaOH. Theorganic layer was washed with sat. NH₄Cl, dried over Na₂SO₄, filteredand evaporated. Purification by silica gel column chromatography elutingwith 0-5% methanol in dichloromethane afforded the desired compound (50mg, 21%), which was converted into its tartrate salt.

R_(f)=0.39 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 527 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) 6 7.22-6.79 (m, 8H, Ar—H), 4.62-4.54 (m, 0.6H, pip-H),4.49 and 4.42 (2s, 2H, benzyl-H), 4.06-3.98 (m, 1H, dioxolane-H),3.75-3.66 (m,4.4H, pip-H, CH_(2OiBu), benzyl-H), 3.48 (m, 2H,dioxolane-H), 2.89-2.83 (m, 2H, pip-H), 2.45-2.25 (m, 2H, NCH₂),2.07-1.99 (m, 2.2H, pip-H, CH_(OiBu)), 1.85-1.51 (m, 6H, pip-H,NCH₂CH₂), 1.36-1.28 (m, 6.8H, C(CH₃)₂, pip-H), 1.02-0.99 (m, 6H,CH_(3OiBu)). HPLC t_(R)=9.3 min.

4-[2-(Tosyloxy)ethyl]-1,3-dioxane (128NLS46-B)

A suspension of 1,3,5-pentanetriol (1.01 g, 8.33 mmol), paraformaldehyde(0.46 g) and methanesulfonic acid (0.33 mL) in DMF (3 mL) is heated for10 min at 130° C. under microwave irradiation. The mixture waspartitioned between ethyl acetate and water, the organic layer driedover Na₂SO₄, filtered and evaporated. The residue was dissolved inmethanol (3 mL), conc. HCl (0.09 mL) added, and the mixture heated at80° C. for 10 min under microwave irradiation. Ethyl acetate and 2M NaOHwere added, the aqueous layer extracted twice with ethyl acetate and thecombined organic layers washed with brine, dried over Na₂SO₄, filteredand evaporated. The crude product was treated with p-tosylchloride andDMAP following literature procedures (Moune et al., J. Org. Chem., 1997,62, 3332). The title compound (1.18 g, 49% overall crude yield) wasobtained as a yellowish oil, which was used without purification.

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine(128NLS52)

To a suspension of 4-piperidone monohydrate hydrochloride (1.26 g, 8.23mmol) in acetonitrile (100 mL), potassium carbonate (3.4 g, 24.6 mmol)was added, followed by the tosylate 128NLS46-B (3.54 g, 12.36 mmol) andsodium iodide (1.85 g, 12.35 mmol) and stirring was continued overnightat 60° C. The mixture was filtered, the filtrate evaporated in vacuo andthe residue partitioned between 1M NaOH and ethyl acetate. The organiclayer was separated, the aqueous layer extracted twice with ethylacetate and the combined organic layers dried over sodium sulphate,filtered and evaporated to dryness. Purification of the residue bysilica gel column chromatography, eluting with a stepwise gradient of0-4% methanol in dichloromethane, afforded1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-one (128NLS50, 1.73 g, 98%).

To a solution of 128NLS50 (1.73 g, 8.13 mmol) in methanol (100 mL) wasadded dropwise 4-fluorobenzylamine (0.93 mL, 8.13 mmol) and acetic acid.Sodium cyanoborohydride (2.15 g, 40 mmol) was added slowly to themixture at 0° C. and stirring was continued at rt overnight. Thereaction mixture was concentrated in vacuo and the residue partitionedbetween dichloromethane and 1M NaOH, the aqueous layer extracted twicewith dichloromethane and the combined organic layers dried over Na₂SO₄,filtered and evaporated to dryness. Purification of the residue by ashort silica gel column chromatography eluting with 0-30% methanol indichloromethane gave the title compound (1.51 g, 58%) as a colourlesssolid.

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate (128NLS62)

Prepared following the same method as described for 117NLS87-A using4-isobutoxyphenylacetyl chloride and 128NLS52 (480 mg, 1.49 mmol).Yield: 458 mg, 60%.

R_(f)=0.36 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 513 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.21-6.80 (m, 8H, Ar—H), 5.01 (d, 1H, J=6.1,dioxane-H), 4.66-4.56 (m, 1.6H, pip-H, dioxane-H) 4.51 and 4.44 (2s, 2H,benzyl-H), 4.09-4.05 (m, 1H, dioxane-H), 3.77 and 3.51 (2s, 2H,benzyl-H), 3.70-3.57 (m, 4.4H, pip-H, dioxane-H, CH_(2OiBu)), 2.91-2.83(m, 2H, pip-H), 2.45-2.34 (m, 2H, NCH₂), 2.10-2.00 (m, 2.2H, pip-H,CH_(OiBu)), 1.85-1.26 (m, 8.8H, pip-H, dioxane-H, NCH₂CH₂), 1.03-1.00(m, 6H, CH_(3OiBu)). HPLC t_(R)=8.8 min.

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethylphenyl)acetamide,tartrate (128NLS54-A)

Prepared following the same method as described for 117NLS87-A using4-trifluorophenylacetyl chloride and 128NLS52 (116 mg, 0.32 mmol).Yield: 52 mg, 32%.

R_(f)=0.42 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 509 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.60-6.90 (m, 8H, Ar—H), 4.99 (d, 1H, J=6.1,dioxane-H), 4.65-4.54 (m, 1.6H, pip-H, dioxane-H), 4.52 and 4.47 (2s,2H, benzyl-H), 4.07-4.04 (m, 1H, dioxane-H), 3.88 (s, 0.8H, benzyl-H),3.69-3.56 (m, 3.6H, benzyl-H, pip-H, dioxane-H), 2.89 (m, 2H, pip-H),2.49-2.31 (m, 2H, NCH₂), 2.07-1.99 (m, 1.2H, pip-H), 1.89-1.36 (m, 8.8H,pip-H, dioxane-H, NCH₂CH₂). HPLC t_(R)=7.3 min.

2-(4-Cyanophenyl)-N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate (128NLS54-C)

4-Cyanophenylacetic acid was synthesized according a method by Jaeger etal. (J. Chem. Soc., 1941, 744-747) and converted to the correspondingacetyl chloride by treatment with oxalylchloride. The title compound wasprepared following the same method as described for 117NLS87-A using4-cyanophenylacetyl chloride and 128NLS52 (116 mg, 0.32 mmol). Yield: 60mg, 40%.

R_(f)=0.40 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 466 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.7:0.3) δ 7.62-6.89 (m, 8H, Ar—H), 4.97 (d, 1H, J=6.1,dioxane-H), 4.63 (m, 1H, dioxane-H), 4.59-4.47 (m, 2.7H, pip-H,benzyl-H), 4.06-4.02 (m, 1H, dioxane-H), 3.86 (s, 0.6H, benzyl-H),3.69-3.55 (m, 3.7H, benzyl-H, pip-H, dioxane-H), 2.91-2.86 (m, 2H,pip-H), 2.47-2.30 (m, 2H, NCH₂), 2.05-1.39 (m, 10H, pip-H, dioxane-H,NCH₂CH₂). HPLC t_(R)=4.3 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide,hydrochloride (69NLS97)

Prepared following the same method as described for 117NLS01 using103NLS56 (240 mg, 0.60 mmol) and 1-(2-tosyloxyethyl)-2-imidazolidinoneas the alkylating agent. Yield: 95 mg, 31%.

LCMS m/z 511 [M+H]⁺.¹H-NMR (CD₃OD, rotamers 0.6:0.4) δ 7.24-6.81 (m, 8H,Ar—H), 4.56 and 4.52 (2s, 2H, benzyl-H), 4.41-4.37 and 3.93-3.88 (m, 1H,pip-H), 3.84 and 3.56 (2s, 2H, benzyl-H), 3.73-3.69 (m, 2H, CH_(2OiBu)),3.46-3.20 (m, 6H, imid-CH₂, NCH₂CH₂), 2.99-2.85 (m, 2H, pip-H), 2.44 (m,2H, NCH₂), 2.10-1.96 (m, 3.2H, pip-H, CH_(OiBu)), 1.67-1.62 (m, 3H,pip-H), 1.30 (m, 0.8H, pip-H), 1.03-0.99 (m, 6H, J=6.6, CH_(3OiBu)).HPLCt_(R)=9.5 min.

Choosing the appropriate secondary amines (prepared in analogy to themethod described for 103NLS56), following compounds were prepared usinga similar procedure:

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide,hydrochloride (63ELH39-B)

LCMS m/z 465 [M+H]⁺.¹H-NMR (CDCl₃, rotamers 0.6:0.4) δ 7.30-6.80 (m,8H), 4.60-4.53 (m, 0.6H), 4.50 and 4.43 (2s, 2H), 3.78 (m, 4.2H), 3.51(s, 1.2H), 3.46-3.24 (m, 6H), 2.92-2.79 (m, 2H), 2.46-2.40 (m, 2H), 2.35and 2.29 (2s, 3H), 2.11-2.05 (m, 1.2H), 1.92-1.86 (m, 0.8H), 1.65-1.50(m, 3.2H, partly covered by HDO signal), 1.31 (m, 0.8H).

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)propyl]piperidin-4-yl}acetamide;hydrochloride (103NLS39)

Prepared following the same method as described for 117NLS01 usingN-(4-fluorobenzyl)-N-(piperidin-4-yl)-2-(4-isoproxyphenyl)acetamide (229mg, 0.59 mmol) and1-(3-chloropropyl)-3-methyl-1,3-dihydrobenzimidazol-2-one as thealkylating agent.

Yield: 205 mg, 61%. R_(f)=0.29 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 573 [M+H]⁺.¹H-NMR (CDCl₃, rotamers 0.5:0.5) δ 7.18-6.78 (m, 12H, Ar—H), 4.59-4.43(m, 3.5H, pip-H, OCH, benzyl-H), 3.88 (t, 2H, J=6.8, NCONCH₂), 3.74 (m,1.5H, pip-H, benzyl-H), 3.49 (s, 1H, benzyl-H), 3.38 and 3.37 (2s, 3H,NCH₃), 2.93-2.79 (m, 2H, pip-H), 2.36-2.29 (m, 2H, NCH₂), 2.02-1.95 (m,1H, pip-H), 1.90-1.46 (m, 6H, pip-H, NCH₂CH₂), 1.31-1.25 (m, 7H, pip-H,CH(CH₃)₂). HPLC t_(R)=8.0 min.

Choosing the appropriate secondary amines (prepared in analogy to themethod described for 103NLS56) and alkylating agents, followingcompounds were prepared using a similar procedure:

N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-2-(4-methoxyphenyl)-N-(4-methylbenzyl)acetamide,hydrochloride (63ELH29A).

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)propyl]piperidin-4-yl}-acetamide,hydrochloride (50ELH89).

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl}N-{1-[4-(2-:oxo-2,3-dihydrobenzoimidazol-1-yl)butyl]piperidin-4-yl}acetamide,hydrochloride (63ELH91).

N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)acetamide,hydrochloride (63ELH89).

4-(4-Fluorobenzylamino)-piperidine-1-carboxylic acid benzyl ester(118AF93-51)

A solution of 4-fluorobenzylamine (5.48 g, 43.8 mmol) in a mixture ofmethanol and acetic acid (5:1, 60 mL) was added dropwise to a solutionof benzyl 4-oxo-1-piperidine carboxylate (10.2 g, 43.8 mmol) in methanol(150 mL) at rt. To this mixture sodium cyanoborohydride (5.50 g, 87.5mmol) was slowly added. After 20 hours stirring at rt the reactionmixture was neutralized and the solvent was removed by evaporation underreduced pressure. The residue was partitioned between dichloromethaneand water. The organic layer was dried over sodium sulphate, filteredand evaporated to dryness. Purification of the residue by silica gelcolumn chromatography, eluting with 7% methanol in dichloromethane,afforded the desired compound (9.0 g, 60 %).

R_(f)=0.56 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 343 [M+H]⁺. HPLC t_(R)=6.2 min.

N-(1-Benzyloxycarbonylpiperidin-4-yl)-N-(4-fluorobenzyl)-N′-(4-isopropoxybenzyl)carbamide(118AF97-120)

1,8-Bis(dimethylamino)-naphtalene (3.19 g, 14.9 mmol) was added to asolution of 4-(isopropoxy)phenyl acetic acid (2.89 g, 14.9 mmol) in drytetrahydrofuran (18 mL) at rt under argon atmosphere. After 25 minutesstirring at rt diphenylphosphoryl azide (4.10 g, 14.9 mmol) was addeddropwise and the mixture refluxed for 6 hours. It was allowed to cool tort and then stored at −20° C. overnight to precipitate out the ammoniumphosphate salt. A mixture of diethyl ether and ethyl acetate (1:1 v/v,25 mL) was added to the cold reaction mixture. The precipitate wasfiltered from the reaction mixture and washed with diethyl ether: ethylacetate (1:1 v/v, 20 mL). The filtrate was evaporated to dryness giving1-isocyanatomethyl-4-isopropoxybenzene as an oil (3.2 g), which was usedin the next step without further purification.

Sodium carbonate (3.5 g, 25.3 mmol) was added to the solution of4-(4-fluorobenzyl amino)-piperidine-1-carboxylic acid benzyl ester118AF93-51 (5.7g, 16.7 mmol) in dry tetrahydrofuran (20 mL). To thissuspension a solution of 1-isocyanatomethyl-4-isopropoxybenzene (3.2 g,16.7 mmol) in dry tetrahydrofuran (10 mL) was added under argonatmosphere. The reaction mixture was stirred overnight at rt. Afterwardsthe mixture was partitioned between dichloromethane and water. Theorganic layer was dried over sodium sulphate, filtered and evaporated todryness. Purification of the residue by silica gel columnchromatography, eluting with 8% methanol in dichloromethane afforded thedesired compound (2.0 g, 22%).

R_(f)=0.36 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 534 [M+H]⁺. HPLC t_(R)=10.2min.

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-piperidin-4-yl-carbamide ,oxalate (118AF99-121)

The desired compound was obtained by hydrogenation of 118AF97-120 (2.0g, 3.75 mmol) in absolute ethanol (100 mL) using palladium on carbon asa catalyst. The product was purified by column chromatography on silicagel eluting with stepwise gradient of 5-10% methanol in dichloromethane.Yield: 1.16 g, 77%.

R_(f)=0.10 (MeOH/CH₂Cl₂ 10:90). LCMS m/z 400 [M+H]⁺. ¹H NMR (CDCl₃) δ7.19 (m, 2H, Ar—H), 7.01-6.69 (m, 4H, Ar—H), 6.76 (m, 2H, Ar—H),4.51-4.40 (m, 3H, pip-H, OCH(CH₃), NH), 4.35 (s, 2H, benzyl-H), 4.28 (s,1H, benzyl-H), 4.27 (s, 1H, benzyl-H), 3.14-3.07 (m, 2H, pip-H),2.74-2.68 (m, 2H, pip-H), 2.10 (broad s, 1H, NH), 1.78-1.70 (m, 2H,pip-H), 1.58-1.48 (m, 2H, pip-H), 1.31 (d, 6H, J=6.0, OCH(CH₃)). HPLCt_(R)=5.9 min.

N-{1-[2-(1,-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isopropoxy-benzyl)carbamide,oxalate (130AF10-147)

Potassium carbonate (0.21 g, 1.50 mmol) was added to a solution of118AF99-121 (0.3 g, 0.75 mmol) in dry N,N-dimethylformamide (2 mL). Thesuspension was shaken for 30 minutes at 58° C. A solution of2-(2-bromoethyl)-1,3-dioxolane (0.163 g, 0.90 mmol) in dryN,N-dimethylformamide (0.4 mL) was added dropwise to the warm suspensionand the heating was continued overnight. The mixture was allowed to coolto rt, then filtered and partitioned between water and dichloromethane.The organic layer was washed with a aqueous solution of 4% magnesiumsulphate and evaporated to dryness. Purification of the residue bysilica gel column chromatography, eluting with 4% methanol indichloromethane, afforded the desired compound (197 mg, 53%). Theproduct was converted to its oxalate form as described above.

R_(f)=0.39 (MeOH/CH₂Cl₂ 4:94). LCMS m/z 500 [M+H]⁺. ¹H NMR (CDCl₃) δ7.17 (m, 2H, Ar—H), 7.00-6.95 (m, 4H, Ar—H), 6.76 (m, 2H, Ar—H), 4.88(t, 1H, J=4.8, dioxolane-H), 4.51-4.44 (m, 2H, NH, CH(CH₃)₂), 4.36-4.26(m, 5H, benzyl-H, pip-H), 3.95-3.80 (m, 4H, dioxolane-H), 2.98-2.91 (m,2H, pip-H), 2.48-2.43 (m, 2H, NCH₂), 2.10-2.01 (m, 2H, pip-H), 1.85-1.79(m, 2H, NCH₂CH₂), 1.76-1.58 (m, 4H, pip-H), 1.30 (d, 6H, J=6.0,CH(CH₃)₂). HPLC t_(R)=6.9 min.

Choosing the appropriate secondary amines (prepared in analogy to themethod described for 103NLS56), following compounds were prepared usingthe same procedure:

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl]-2-(4-methoxyphenyl)-N-(4-methylbenzyl)acetamide,hydrochloride (63ELH29B).

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,hydrochloride (74AKU06-2).

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-isopropoxyphenyl1N-(4-methylbenzyl)acetamide,hydrochloride (76ELH07).

N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide,tartrate (38PH50).

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidin-4-yl}carbamide,oxalate (130AF12-148)

4 M HCl (0.5 mL) and water (0.5 mL) were added to a solution of130AF10-147 (50 mg, 0.10 mmol) in 1.4-dioxane (1 mL). The mixture wasstirred in a sealed flask for 10 minutes under microwave irradiation at120° C. Afterwards the mixture was partitioned between dichloromethaneand water. The organic layer was dried over sodium sulphate, filteredand evaporated to dryness. The residue was dissolved in 1.4-dioxane (1mL) and a solution of (S)-(+)-propylene glycol (39 mg, 0.51 mmol) in1.4-dioxane (0.5 mL) was added. After addition of HCl (4M in dioxane,0.5 mL) the mixture was stirred in a sealed flask for 20 minutes undermicrowave irradiation at 120° C. The mixture was partitioned betweensaturated sodium bicarbonate solution and dichloromethane. The organiclayer was evaporated to dryness. Purification of the residue by silicagel column chromatography, eluting with a stepwise gradient of 4-8%methanol in dichloromethane afforded the desired compound (2.1 mg, 4%).The product was converted to its oxalate form as described above.

R_(f)=0.36 (MeOH/CH₂Cl₂ 4:94). LCMS m/z 514 [M+H]⁺. HPLC t_(R)=7.2 min.

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-[1-(3-morpholin-4-yl-propyl)piperidin-4-yl]carbamideoxalate (130AF09-145)

A solution of 1-chloro-3-bromopropane in dry tetrahydrofuran (2 mL) wasadded to a cold suspension of morpholine (200 mg, 2.29 mmol) and sodiumcarbonate (0.63 g, 4.56 mmol) in dry tetrahydrofuran (8 mL) at 0° C. Themixture was stirred at 45° C. overnight. The mixture was allowed to coolto rt, filtered and evaporated to dryness. Purification of the residueby silica gel column chromatography, eluting with a mixture of ethylacetate and n-heptane (70:30), afforded3-chloro-1-morpholin-4-yl-propane (156 mg, 42 %).

A solution of 3-chloro-1-morpholin-4-yl-propane (7.6 mg, 0.046 mmol) indry N,N-dimethylformamide (0.10 mL) was added to a solution of118AF99-121 (15 mg, 0.037 mmol) and caesium carbonate (40 mg, 0.123mmol) in a mixture of dry N,N-dimethylformamide and acetonitrile (1:2,0.30 mL). After addition of sodium iodide (7.0 mg, 0.047 mmol) themixture was shaken overnight at 60° C. The mixture was allowed to coolto rt. Acetonitrile was removed by evaporation under reduced pressureand the residue was partitioned between dichloromethane (2 mL) and water(1 mL). The organic layer was evaporated to dryness. Purification of theresidue by preparative reversed phase HPLC (C₁₈) afforded the desiredcompound (6.1 mg, 32%).

LCMS m/z 527 [M+H]⁺. HPLC t_(R)=6.2 min.

Choosing the appropriate secondary amines (prepared in analogy to themethod described for 103NLS56), following compounds were prepared usinga simkilar procedure:

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholin-4-ylethyl)piperidin-4-yl]acetamide,dihydrochloride (63ELH40-2).

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(3-morpholin-4-ylpropyl)piperidin-4-yl]acetamide,dihydrochloride (63ELH41-2).

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-[1-(3-morpholin-4-ylpropyl)piperidin-4-yl]acetamide,dihydrochloride (74AKU07-2).

N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl>N-[1-(3-morpholin-4-yl-propyl)piperidin-4-yl]acetamide,dihydrochloride (76ELH14-A).

N-(4-Fluorobenzal)-N′-(4-isopropoxybenzyl)-N-[1-(3-piperidin-1-yl-propyl)piperidin-4-yl]carbamide,oxalate (13 OAF09-146)

The desired compound was synthesized from piperidine,1-chloro-3-bromopropane and 118AF99-121 (15 mg, 0.037 mmol) using thesame method as for preparation of 130AF09-145. Yield: 5.8 mg, 30%.

LCMS m/z 525 [M+H]⁺. HPLC t_(R)=6.8 min.

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-[1-(3-((S)-4-isopropyl-2-oxazolidinon-1-yl-propyl)piperidin-4-yl]carbamide,tartrate (130AF 14-152)

The desired compound was synthesized from(4S)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one 103NLS94 (7.4 mg,0.045 mmol) and 118AF99-121 (15 mg, 0.037 mmol) using the same method asfor preparation of 130AF09-145. Yield: 3.3 mg, 16%.

LCMS m/z 569 [M+H]⁺. HPLC t_(R)=8.2 min.

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{1-[2-(2,5.5-trimethyl-1,3-dioxan-2-yl)ethyl]}piperidin-4-yl]carbamide,oxalate (130AF07-143)

The desired compound was synthesized from2-bromo-1-(2,5,5-trimethyl-1,3-dioxan-2-yl)-ethane (10.7 mg, 0.045 mmol)and 118AF99-121 (15 mg, 0.037 mmol) using the same method as forpreparation of 130AF09-145. Yield: 8.3 mg, 15%.

LCMS m/z 556 [M+H]⁺. HPLC t_(R)=9.6 min.

N-{1-[3-(1,3-Dioxolan-2-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isopropoxybenzyl)carbamide,oxalate (13 OAF07-131)

The desired compound was synthesized from3-chloro-1-(1,3-dioxolan-2-yl)-propane (6.79 mg, 0.045 mmol) and118AF99-121 (15 mg, 0.037 mmol) using the same method as for preparationof 130AF09-145. Yield: 5.6 mg, 11%.

LCMS m/z 514 [M+H]⁺. HPLC t_(R)=8.3 min.

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-N′-(4-isopropoxybenzyl)carbamide,oxalate (13 OAF05-129)

A solution of 2,2-dimethyl-1,3-dioxan-5-one (9.75 mg, 0.075 mmol) inmethanol (0.10 mL) was added to a solution of 118AF99-121 (15 mg, 0.037mmol) in methanol (0.10 mL). The reaction mixture was stirred at rtafter addition of acetic acid (60 μL of 1 M solution in methanol). After2 h stirring a solution of sodium cyanoborohydride (5 mg, 0.079 mmol) inmethanol (0.10 mL) was added and stirring was continued overnight at rt.The solvent was removed by evaporation under reduced pressure and theresidue partitioned between 2 M aq. sodium hydroxide anddichloromethane. The layers were separated by filtration over PTFEfilter. The organic layer was evaporated to dryness. Purification of theresidue by preparative reversed phase HPLC (C₁₈) afforded the desiredcompound (2.3 mg, 12%).

LCMS m/z 514 [M+H]⁺. HPLC t_(R)=9.0 min.

N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{[2-(1-methylpyrrolidin-2-yl)ethyl]-piperidin-4-yl}carbamide, oxalate (130AF07-135)

The desired compound was synthesized from2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (7.7 mg, 0.041 mmol)and 118AF99-121 (15 mg, 0.037 mmol) using the same method as for thepreparation of 130AF09-145. Yield: 4.4 mg, 23%.

LCMS m/z 511 [M+H]⁺. HPLC t_(R)=7.0 min.

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzal)-2-(4-isobutoxyphenyl)acetamide,oxalate (130AF22-105)

A solution of 2,2-dimethyl-1,3-dioxan-5-one (81 mg, 0.62 mmol) inmethanol (10 mL) was added dropwise to a solution of 103NLS56 (179 mg,0.45 mmol) in methanol (10 mL). The reaction mixture was stirred at rtafter addition of acetic acid (200 μL). After 2 hours sodiumcyanoborohydride (56 mg, 0.90 mmol) was slowly added and stirring wascontinued overnight at rt. The mixture was neutralized with few drops of2 M aq sodium hydroxide. The solvent was removed by evaporation underreduced pressure and the residue partitioned between water anddichloromethane. The organic layer was dried over sodium sulphate,filtered and evaporated to dryness. Purification of the residue bysilica gel column chromatography, eluting with 6% methanol indichloromethane, afforded the desired compound (98 mg, 43%).

R_(f)=0.32 (MeOH/CH₂Cl₂, 6:94). LCMS m/z 513 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.26-6.79 (m, 8H, Ar—H), 4.63-4.54 (m, 0.6H, pip-H),4.50 & 4.43 (2s, 2H, benzyl-H), 3.91 & 3.88 (2d, 1H, J=5.6, dioxane-H),3.79-3.67 (m, 6.2 H, dioxane-H, benzyl-H, pip-H, CH_(2OiBu)), 3.51 (s,l.2H, benzyl-H), 2.98-2.88 (m, 2H, pip-H), 2.64-2.52 (m, 1H, dioxane-H),2.38-2.28 (m, 1.2H, pip-H), 2.17-2.00 (m, 1.8H, CH(CH₃)₂, pip-H),1.72-1.47 (m, 3.2H, pip-H), 1.43 (m, 0.8H, pip-H), 1.38-1.22 (m, 6H,dioxane-CH₃), 1.01 (m, 6H, CH(CH₃)₂). HPLC t_(R)=10.0 min.

N-[1-(1,3-Dioxan-5-yl)-piperidin-4-yl)-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl-acetamide,tartrate (130AF26-164)

3 M aq HCl (1 mL) and water (1 mL) were added to a solution of130AF22-105 (98.2 mg, 0.19 mmol) in 1.4-dioxane (2 mL) and the mixturestirred in a sealed flask under microwave irradiation for 10 minutes at120° C. The mixture was partitioned between water and dichloromethaneand the organic layer dried over sodium sulphate, filtered andevaporated to dryness. The residue was dissolved in 1.4-dioxane (2 mL).To this solution a solution of formaldehyde (37% water solution, 101 mg,1.16 mmol) in 1.4-dioxane (0.5 mL) was added. The reaction mixture wasstirred in a sealed flask for 30 minutes under microwave irradiation at120° C. Molecular sieves (4 Å) were added to the reaction mixture at rtand removed after 24 hours. The mixture was heated for an additional 20minutes at 120° C. under microwave irradiation and partitioned betweendichloromethane and sodium bicarbonate. The organic layer was dried oversodium sulphate, filtered and evaporated to dryness. Purification of theresidue by silica gel column chromatography, eluting with 6% methanol indichloromethane, afforded the desired compound (17 mg, 18%). The productwas converted to its tartrate form as described above.

R_(f)=0.30 (MeOH/CH₂Cl₂, 6:94). LCMS m/z 485 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.21-6.80 (m, 8H, Ar—H), 4.88 (m, 1H, dioxane-H),4.61-4.56 (m, 1.6H, dioxane-H, pip-H), 4.50 & 4.43 (2s, 2H, benzyl-H),4.12-4.06 (m, 2H, dioxane-H) 3.85-3.60 (m, 5.2 H, dioxane-H, benzyl-H,pip-H, CH_(2OiBu)), 3.51 (s, 1.2H, benzyl-H), 2.94-2.86 (m, 2H, pip-H),2.59-2.48 (m, 1H, dioxane-H), 2.37-2.28 (m, 1.2H, pip-H), 2.17-2.01 (m,1.8H, CH(CH₃)₂, pip-H), 1.68-1.46 (m, 3.2H, pip-H), 1.46-1.30 (m, 0.8H,pip-H), 1.02 (m, 6H, CH(CH₃)₂). HPLC t_(R)=9.5 min.

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate (130AF35-168)

The desired compound was synthesized from 2,2-dimethyl-1,3-dioxan-5-one(59 mg, 0.45 mmol) andN-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide (83 mg,0.24 mmol) using the same method as for preparation of 130AF22-105. Thestarting materialN-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide wasprepared in the same way as 103NLS56.

R_(f)=0.26 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 459 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.28-6.91 (m, 8H, Ar—H), 4.63-4.52 (m, 0.6H, pip-H),4.51 & 4.46 (2s, 2H, benzyl-H), 3.92-3.88 (m, 2H, dioxane-H), 3.82-3.69(m, 3.2 H, dioxane-H, benzyl-H, pip-H), 3.54 (s, 1.2H, benzyl-H),2.99-2.90 (m, 2H, pip-H), 2.62-2.51 (m, 1H, dioxane-H), 2.39-2.28 (m,1.2H, pip-H), 2.18-2.10 (m, 0.8H, pip-H), 1.72-1.50 (m, 3.2H, pip-H),1.42-1.31 (m, 6.8H, pip-H, dioxane-CH₃). HPLC t_(R)=7.9 min.

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate (130AF41-171)

The starting materialN-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide wasprepared in the same way as 103NLS56.

Potassium carbonate (64 mg, 0.46 mmol) was added to a solution ofN-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide (79.4mg, 0.23 mmol) in dry N,N-dimethylformamide (3 mL). To this suspension asolution of 4-[2-(tosyloxy)ethyl]-1,3-dioxane 128NLS46B (99 mg, 0.35mmol) in dry N,N-dimethylformamide (1 mL) was added dropwise at rt. Thereaction mixture was stirred overnight at 60° C. and it was partitionedbetween dichloromethane and water. The organic layer was dried oversodium sulphate, filtered and evaporated to dryness. Purification of theresidue by silica gel column chromatography, eluting with stepwisegradient of 2-5% methanol in dichloromethane, afforded the desiredproduct (71 mg, 67%). The product was converted to its tartrate form asdescribed above.

R_(f)=0.41 (MeOH/CH₂Cl₂, 6:96). LCMS m/z 459 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.28-6.90 (m, 8H, Ar—H), 4.99 (m, 1H, dioxane-H),4.77-4.64 (m, 1.6H, pip-H, dioxane-H), 4.52 (s, 2H, benzyl-H), 3.80-3.56(m, 4.4H, dioxane-H, benzyl-H, pip-H), 3.21-3.08 (m, 1.2H, pip-H),2.96-2.88 (m, 0.8H, pip-H), 2.75-2.56 (m, 1.2H, NCH₂), 2.52-2.24 (m, 2H,pip-H, NCH₂), 2.04-1.30 (m, 9.8H, pip-H, NCH₂CH₂, dioxane-H). HPLCt_(R)=6.4 min.

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxyphenyl)acetamide,tartrate (130AF80-186)

Triethylamine (125 μL, 0.89 mmol) was added to a solution ofN-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine128NLS52 (96 mg, 0.30 mmol) in dry dichloromethane (5 mL) at rt. Thesolution was cooled to −10° C. and a solution of(4-trifluoromethoxyphenyl)acetyl chloride (71 mg, 0.30 mmol) in drydichloromethane (1 mL) was added dropwise. The reaction mixture wasstirred overnight at rt. The solvent was removed by evaporation underreduced pressure. The residue was suspended in tetrahydrofuran andfiltered. The filtrate was evaporated to dryness and the residue waspurified by silica gel column chromatography, eluting with 4% methanolin dichloromethane, to give the desired compound (46 mg, 30%). Thecompound was converted to its tartrate form as described above.

R_(f)=0.33 (MeOH/CH₂Cl₂, 6:94). LCMS m/z 459 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.34-6.91 (m, 8H, Ar—H), 5.01 (d, 1H, J=6.0,dioxane-H), 4.66-4.54 (m, 1.6H, pip-H, dioxane-H), 4.52 & 4.49 (2s, 2H,benzyl-H), 4.09-4.05 (m, 1H, dioxane-H), 3.83 (s, 0.8H, benzyl-H),3.72-3.56 (m, 3.6 H, dioxane-H, benzyl-H, pip-H), 2.94-2.86 (m, 2H,pip-H), 2.50-2.32 (m, 2H, NCH₂), 2.11-2.00 (m, 1.2H, pip-H), 1.90-1.52(m, 8.8H, pip-H, NCH₂CH₂, dioxane-H). HPLC t_(R)=7.6 min.

N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzal)-2-(4-propoxyphenyl)acetamide,tartrate (130AF71-184)

Triethylamine (163 μL, 1.17 mmol) was added to a solution ofN-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine128NLS52 (126 mg, 0.39 mmol) in dry dichloromethane (5 mL) at rt. Thesolution was cooled to −15° C. and a solution of (4-propoxyphenyl)acetylchloride (92 mg, 0.43 mmol) in dry dichloromethane (2 mL) was addeddropwise. The reaction mixture was stirred for 2 hours at rt. Thesolvent was removed by evaporation under reduced pressure. The residuewas suspended in tetrahydrofuran and filtered. The filtrate wasevaporated to dryness and the residue was purified by silica gel columnchromatography, eluting with a stepwise gradient of 0-4% methanol indichloromethane, to give the desired compound (66 mg, 34%). The productwas converted to its tartrate form as described above.

R_(f)=0.16 (MeOH/CH₂Cl₂, 4:96). LCMS m/z 499 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.21-6.78 (m, 8H, Ar—H), 5.00 (m, 1H, dioxane-H),4.66-4.54 (m, 1.6H, pip-H, dioxane-H), 4.50 & 4.44 (2s, 2H, benzyl-H),4.10-4.03 (m, 1H, dioxane-H), 3.92-3.87 (m, 2H, OCH_(2OPr)), 3.78-3.50(m, 4.4 H, dioxane-H, benzyl-H, pip-H), 2.92-2.82 (m, 2H, pip-H),2.50-2.29 (m, 2H, NCH₂), 2.09-1.98 (m, 1.2H, pip-H), 1.88-1.27 (m,10.8H, pip-H, NCH₂CH₂, dioxane-H, CH_(2OPr)), 1.05-099 (m, 3H,CH_(3OPr)). HPLC t_(R)=7.6 min.

N-(4-Fluorobenzal)-2-(4-isobutoxyphenyl)-N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]acetamide,tartrate (130AF33-166)

A solution of tetrahydro-4H-pyran-4-one (43 mg, 0.42 mmol) in methanol(1 mL) was added to a solution of 103NLS56 (57 mg, 0.14 mmol) inmethanol (2 mL). After addition of acetic acid (100 μL) the reactionmixture was stirred for 15 minutes in a sealed flask under microwaveirradiation at 100° C. Afterwards sodium cyanoborohydride (26 mg, 0.42mmol) was added to the mixture and stirring was continued for additional60 min under microwave irradiation at 80° C. The mixture was passed overan acidic ion-exchange SPE cartridge. Further purification of theproduct by silica gel column chromatography, eluting with a stepwisegradient of 2-5% methanol in dichloromethane, afforded the desiredcompound (19.2 mg, 28%). The compound was converted to its tartrate formas described above.

R_(f)=0.18 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 483 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.21-6.80 (m, 8H, Ar—H), 4.64-4.56 (m, 0.6H, pip-H),4.51& 4.45 (2s, 2H, benzyl-H), 4.02-3.96 (m, 2H, THP—H), 3.77-3.68 (m,3.2H, benzyl-H, CH_(2OiBu), pip-H), 3.51 (s, 1.2H, benzyl-H), 3.30 (t,2H, J=12.0, THP—H), 2.98-2.88 (m, 2H, pip-H), 2.46-2.34 (m, 1H, THP—H),2.28-2.19 (m, 1.2H, pip-H), 2.10-1.99 (m, 1.8H, CH_(OiBu), pip-H),1.73-1.47 (m, 7.2H, pip-H, THP—H), 1.39-1.33 (m, 0.8H, pip-H), 1.01 (m,6H, CH_(3OiBu)). HPLC t_(R)=8.0 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxylphenyl)-N-[1-(tetrahydropyran-4-ylmethyl)piperidin-4-yl]acetamide,tartrate (130AF82-187)

The title compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56(110 mg, 0.27 mmol) and tetrahydro-2H-pyran-4-yl carbaldehyde (63 mg,0.55 mmol) using the same method as for preparation of 130AF33-166.Yield: 18 mg, 13%.

R_(f)=0.30 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 497 [M+H]⁺. HPLC t_(R)=8.4 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-{1-[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl]acetamide,tartrate (130AF83-188)

The title compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56(110 mg, 0.27 mmol) and tetrahydro-2H-pyran-4-yl acetalaldehyde (70.5mg, 0.55 mmol) using the same method as for preparation of 130AF33-166.Yield: 40 mg, 29%.

R_(f)=0.30 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 511 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.21-6.80 (m, 8H, Ar—H), 4.65-4.55 (m, 0.6H, pip-H),4.51& 4.44 (2s, 2H, benzyl-H), 3.95-3.89 (m, 2H, THP—H), 3.78-3.66 (m,3.2H, benzyl-H, CH_(2OiBu), pip-H), 3.51 (s, 1.2H, benzyl-H), 3.34 (t,2H, J=12.0, THP—H), 2.92-2.82 (m, 2H, pip-H), 2.34-2.26 (m, 2H,NCH₂CH₂), 2.11-1.96 (m, 2.2H, pip-H, CH_(OiBu)), 1.84-1.20 (m, 11.8H,pip-H, THP—H, CH₂CH₂N), 1.02 (m, 6H, CH_(3OiBu)). HPLC t_(R)=8.2 min.

N-(4-Fluorobenzyl)-2-(4-fluorophenyl)-N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]acetamide,tartrate (130AF37-169)

The desired compound was synthesized from tetrahydro-4H-pyran-4-one andN-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide usingthe same method as for preparation of 130AF33-166. The starting materialN-(4-fluorobenzyl)-2-(4-fluorophenyl)-N-piperidin-4-yl-acetamide wasprepared in the same way as 103NLS56.

R_(f)=0.29 (MeOH7CH₂Cl₂, 5:95). LCMS m/z 429 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.29-6.91 (m, 8H, Ar—H), 4.64-4.55 (m, 0.6H, pip-H),4.52 & 4.48 (2s, 2H, benzyl-H), 4.02-3.95 (m, 2H, THP—H), 3.80 (s, 0.8H,benzyl-H), 3.75-3.64 (m, 0.4H, pip-H), 3.54 (s, 1.2H, benzyl-H), 3.34(t, 2H, J=12.0, THP—H), 2.99-2.90 (m, 2H, pip-H), 2.48-2.36 (m, 1H,THP—H), 2.26-2.20 (m, 1.2H, pip-H), 2.08-2.00 (m, 0.8H, pip-H),1.76-1.47 (m, 7.2H, pip-H, THP—H), 1.41-1.34 (m, 0.8H, pip-H). HPLCt_(R)=5.6 min.

N-[1-((S)-3,5-Dihydroxypentyl)piperidine-4-yl]-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate (130AF65-182)

The compound (R)-5-[(4-methylbenzenesulfonyl)oxy]pentane-1,3-diol wassynthesized according to Moune et al (J. Org. Chem., 1997, 62,3332-3339). Potassium carbonate (83 mg, 0.60 mmol) was added to asolution of 103NLS56 (94 mg, 0.24 mmol) in dry N,N-dimethylformamide (3mL). To this suspension a solution of(R)-5-[(4-methyl-benzenesulfonyl)oxy]pentane-1,3-diol (82 mg, 0.28 mmol)in dry N,N-dimethylformamide (1 mL) was added, followed by addition ofsodium iodide (43 mg, 0.29 mmol). The reaction mixture was stirredovernight at 60° C. It was allowed to cool to rt, filtered andevaporated to dryness. The residue was partitioned betweendichloromethane and 2M aq sodium hydroxide. The organic layer was driedover sodium sulphate, filtered and evaporated to dryness. Purificationof the residue by silica gel column chromatography, eluting with astepwise gradient of 6-10% methanol in dichloromethane, afforded thedesired compound (35 mg, 29%), which was converted to its tartrate formas described above.

R_(f)=0.48 (MeOH/CH₂Cl₂, 10:90). LCMS m/z 501 [M+H]⁺. HPLC t_(R)=7.4min.

N-{1-[2-((4S)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate (130AF67-183)

Paraformaldehyde (9 mg, 0.28 mmol) and hydrochloric acid (4M in1.4-dioxane, 0.5 mL) were added to a solution of tartaric acid salt of130AF65-182 (37 mg, 0.056 mmol) in 1.4-dioxane. The reaction mixture wasstirred for 2 hours in a sealed flask under microwave irradiation at120° C. and partitioned between dichloromethane and sodium bicarbonate.The organic layer was washed with brine, dried over sodium sulphate,filtered and evaporated to dryness. Purification of the residue byacidic ion-exchange SPE cartridge afforded the desired compound (9.0 mg,31%), which was converted to its tartrate form as described above. Theenantiomeric excess (ee) was determined to be 94% using chiral HPLCanalysis (Chiralpak AD column, 4.6×250 mm; heptane/I-PrOH 50:50, 0.3%DEA; 0.5 mL/min; t_(R) 20.5 min).

R_(f)=0.41 (MeOH/CH₂Cl₂, 8:92). LCMS m/z 513 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.21-6.80 (m, 8H, Ar—H), 5.00 (m, 1H, dioxane-H),4.68-4.54 (m, 1.6H, pip-H, dioxane-H), 4.51 & 4.45 (2s, 2H, benzyl-H),4.06 (m, 1H, dioxane-H), 3.77-3.48 (m, 6.4H, dioxane-H, benzyl-H,CH_(2OiBu), pip-H), 2.98-2.79 (m, 2H, pip-H), 2.50-2.58 (m, 2H, NCH₂),2.14-1.99 (m, 2.2H, CH_(OiBu), pip-H), 1.90-1.25 (m, 8.8H, pip-H,NCH₂CH₂, dioxane-H), 1.02 (m, 6H, CH_(3OiBu)). HPLC t_(R)=8.7 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine(118AF52-95)

Sodium carbonate (17.4 g, 125.9 mmol) was added to a solution of4-piperidone monohydrate hydrochloride (6.45 g, 42.0 mmol) inacetonitrile (200 mL). After 30 minutes stirring at rt a solution of2-(2-bromoethyl)-1,3-dioxane (8.45 g, 43.3 mmol) in acetonitrile (50 mL)was added dropwise to the reaction mixture and stirring was continuedovernight at rt and at reflux for an additional 2 hours. The solvent wasremoved by evaporation under reduced pressure and the residue waspartitioned between water and dichloromethane. The organic layer wasdried over sodium sulphate, filtered and evaporated to dryness.Purification of the residue by silica gel column chromatography, elutingwith 7% methanol in dichloromethane, afforded1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-one (6.19 g, 69%).

A solution of 1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-one (6.19 g, 29mmol) in methanol (80 mL) was added dropwise to a solution of4-fluorobenzylamine (3.9 mL, 34 mmol) in methanol (100 mL) under argonatmosphere at rt. After 30 minutes stirring at rt the reaction mixturewas acidified (pH=5) with acetic acid and cooled to 0° C. Sodiumcyanoborohydride (2.15 g, 40 mmol) was added slowly to the cold mixtureand stirring was continued at rt overnight. The reaction mixture wasbasified with 2M NaOH and concentrated in vacuo. The residue waspartitioned between ethyl acetate and water. The organic layer was driedover sodium sulphate, filtered and evaporated to dryness. The residuewas dissolved in abs. ethanol (57 mL). A solution of maleic acid (3.31g, 28.5 mmol) in abs. ethanol (60 mL) was added to this solutionresulting in precipitate formation. The precipitate was collected byfiltration and converted to the free base by a basic extraction. Yield:8.5 g, 91%.

R_(f)=0.29 (MeOH/CH₂Cl₂, 7:93). LCMS m/z 323 [M+H]⁺.¹H NMR (CDCl₃) δ7.25 (m, 2H, Ar—H), 6.95 (m, 2H, Ar—H), 4.54 (t, 1H, J=5.6, dioxane-H),4.07-4.02 (m, 2H, dioxane-H), 3.73-3.67 (m, 4H, dioxane-H, benzyl-H),2.85-2.79 (m, 2H, pip-H), 2.49-2.37 (m, 3H, NCH₂, pip-H), 2.05-1.72 (m,7H, pip-H, NCH₂CH₂, dioxane-H), 1.44-1.25 (m, 4H, dioxane-H, pip-H, NH).HPLC t_(R)=1.4 min.

2-(4-Benzyloxyphenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamidetartrate (118AF66-102)

A solution of triethylamine (0.89 mL, 6.38 mmol) and 118AF52-95 (0.80 g,2.48 mmol) in dry THF (10 mL) was cooled to 0° C. A solution of4-benzyloxyphenylacetyl chloride (0.72 g, 2.76 mmol) was added dropwiseto the cold reaction mixture and stirring was continued at rt for 2 h.The reaction mixture was filtered and the filtrate evaporated todryness. Purification of the residue by silica gel columnchromatography, eluting with a stepwise gradient of 0-6% methanol indichloromethane afforded the desired compound (0.53 g, 39%), which wasconverted to its tartrate form as described above.

R_(f)=0.27 (MeOH/CH₂Cl₂, 7:93). LCMS m/z 547 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.46-6.86 (m, 13H, Ar—H), 5.08-5-02 (m, 2H, PhCH₂O),4.64-4.42 (m, 3.6H, pip-H, benzyl-H, dioxane-H), 4.11-4.02 (m, 2H,dioxane-H), 3.79-3.67 (m, 3.2H, dioxane-H, benzyl-H, pip-H), 3.50 (s,1.2H, benzyl-H), 2.94-2.80 (m, 2H, pip-H), 2.46-2.34 (m, 2H, NCH₂),2.12-1.98 (m, 2.2H, dioxane-H, pip-H), 1.87-1.50 (m, 6H, pip-H,NCH₂CH₂), 1.36-1.24 (m, 1.8H, pip-H, dioxane-H). HPLC t_(R)=8.9 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-hydroxyphenyl)-acetamide,tartrate (118AF67-103)

The desired compound was afforded by hydrogenation of 118AF66-102 (0.50g, 0.92 mmol) in absolute ethanol (200 mL) using palladium on carbon asa catalyst. The product was purified by column chromatography on silicagel eluting with a stepwise gradient of 3-6% methanol indichloromethane. The desired compound (0.22 g, 53%) was converted to itstartrate form as described above.

R_(f)=0.30 (MeOH/CH₂Cl₂, 6:94). LCMS m/z 457 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.13-6.86 (m, 6H, Ar—H), 6.72-6.64 (m, 2H, Ar—H),4.66-4.57 (m, 0.6H, pip-H), 4.54 (m, 1H, dioxane-H), 4.48 & 4.37 (2s,2H, benzyl-H), 4.08-4.01 (m, 2H, dioxane-H), 3.80-3.66 (m, 3.2H,dioxane-H, benzyl-H, pip-H), 3.47 (m, 1.2H, benzyl-H), 2.94-2.82 (m, 2H,pip-H), 2.47-2.39 (m, 2H, NCH₂), 2.10-1.97 (m, 2.2H, dioxane-H, pip-H),1.88-1.53 (m, 6H, pip-H, NCH₂CH₂), 1.34-1.25 (m, 1.8H, pip-H,dioxane-H). HPLC t_(R)=3.0 min.

I.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-methoxyphenyl)-acetamide,tartrate (118AF60-96)

A solution of triethylamine (0.57 mL, 4.09 mmol) and 118AF52-95 (328 mg,1.02 mmol) in dry THF (5 mL) was cooled to 0° C. A solution of4-methoxyphenylacetyl chloride (376 mg, 2.04 mmol) was added dropwise tothe cold reaction mixture and stirring was continued for 20 h at rt. Thereaction mixture was partitioned between 2M NaOH and water. The organiclayer was dried over sodium sulphate, filtered and evaporated todryness. The residue was purified by silica gel column chromatography,eluting with a stepwise gradient of 0-6% methanol in dichloromethane.Final purification of the product by acidic ion-exchange SPE cartridgeafforded the desired compound (153 mg, 33%), which was converted to itstartrate form as described above.

R_(f)=0.40 (MeOH/CH₂Cl₂, 4:96). LCMS m/z 471 [M+H]⁺. ¹H NMR(CDCl₃,rotamers 0.4:0.6) δ 7.24-6.79 (m, 8H, Ar—H), 4.63-4.54 (m, 0.6H,pip-H), 4.52 (t, 1H, J=5.2, dioxane-H), 4.49 & 4.44 (2s, 2H, benzyl-H),4.09-4.01 (m, 2H, dioxane-H), 3.79-3.68 (m, 6.2H, dioxane-H, benzyl-H,pip-H, OCH₃), 3.50 (m, 1.2H, benzyl-H), 2.91-2.80 (m, 2H, pip-H),2.43-2.36 (m, 2H, NCH₂), 2.10-1.98 (m, 2.2H, dioxane-H, pip-H),1.86-1.51 (m, 6H, pip-H, NCH₂CH₂), 1.34-1.26 (m, 1.8H, pip-H,dioxane-H). HPLC t_(R)=7.0 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropylphenyl)-acetamide.tartrate (118AF63-100)

The desired compound was synthesized from 118AF52-95 (400 mg, 1.24 mmol)and 4-isopropylphenylacetyl chloride (340 mg, 1.73 mmol) using the samemethod as for preparation of 118AF66-102. Further purification by acidicion-exchange SPE cartridge was performed. Yield: 273 mg, 46%.

R_(f)=0.34 (MeOH/CH₂Cl₂, 7:93). LCMS m/z 483 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.22-6.89 (m, 8H, Ar—H), 4.64-4.43 (m, 3.6H, pip-H,dioxane-H, benzyl-H), 4.09-4.02 (m, 2H, dioxane-H), 3.79 (s, 0.8H,benzyl-H), 3.76-3.66 (m, 2.4H, dioxane-H, pip-H), 3.54 (m, 1.2H,benzyl-H), 2.92-2.79 (m, 3H, pip-H, CH(CH₃)₂), 2.41-2.35 (m, 2H, NCH₂),2.12-1.98 (m, 2.2H, dioxane-H, pip-H), 1.85-1.49 (m, 6H, pip-H,NCH₂CH₂), 1.34-1.19 (m, 7.8H, pip-H, dioxane-H, CH(CH₃)₂). HPLCt_(R)=8.6 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxy-phenyl)acetamide,tartrate (118AF58-98)

The desired compound was synthesized from 118AF52-95 (328 mg, 1.02 mmol)and 4-trifluoromethoxyphenylacetyl chloride (345 mg, 1.44 mmol) usingthe same method as for preparation of 118AF66-102. Yield: 267 mg, 49%.

R_(f)=0.31 (MeOH/CH₂Cl₂, 4:96). LCMS m/z 525 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.30-6.90 (m, 8H, Ar—H), 4.63-4.48 (m, 3.6H, pip-H,dioxane-H, benzyl-H), 4.05 (m, 2H, dioxane-H), 3.82 (s, 0.8H, benzyl-H),3.76-3.62 (m, 2.4H, dioxane-H, pip-H), 3.55 (m, 1.2H, benzyl-H),2.92-2.84 (m, 2H, pip-H), 2.43-2.36 (m, 2H, NCH₂), 2.10-1.96 (m, 2.2H,dioxane-H, pip-H), 1.88-1.79 (m, 0.8H, pip-H), 1.76-1.52 (m, 5.2H,pip-H, NCH₂CH₂), 1.38-1.26 (m, 1.8H, pip-H, dioxane-H). HPLC t_(R)=8.4min.

II.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-ethoxyphenyl)-acetamide,oxalate (118AF68-104)

The desired compound was synthesized from 118AF52-95 (400 mg, 1.24 mmol)and 4-ethoxyphenylacetyl chloride (300 mg, 1.51 mmol) using the samemethod as for preparation of 118AF66-102. Further purification by acidicion-exchange SPE cartridge was performed. Yield: 0.15 g, 25%.

R_(f)=0.26 (MeOH/CH₂Cl₂, 6:94). LCMS m/z 485 [M+H]⁺. ¹H NMR(CDCl₃,rotamers 0.4:0.6) δ 7.20-6.79 (m, 8H, Ar—H), 4.64-4.54 (m, 0.6H,pip-H), 4.52 (t, 1H, J=5.2, dioxane-H), 4.49 & 4.43 (2s, 2H, benzyl-H),4.07-3.97 (m, 4H, dioxane-H, OCH₂), 3.76-3.66 (m, 3.2H, dioxane-H,pip-H, benzyl-H), 3.49 (s, 1.2H, benzyl-H), 2.91-2.80 (m, 2H, pip-H),2.42-2.32 (m, 2H, NCH₂), 2.10-1.97 (m, 2.2H, dioxane-H, pip-H),1.86-1.48 (m, 6H, pip-H, NCH₂CH₂), 1.42-1.36 (m, 3H, CH₃), 1.34-1.24 (m,1.8H, pip-H, dioxane-H). HPLC t_(R)=7.6 min.

III.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)-acetamide,oxalate (118AF73-107)

The desired compound was synthesized from 118AF52-95 (400 mg, 1.24 mmol)and 4-isopropoxyphenylacetyl chloride (340 mg, 1.60 mmol) using the samemethod as for preparation of 118AF66-102. Further purification by acidicion-exchange SPE cartridge was performed. Yield: 91 mg, 15%.

R_(f)=0.58 (MeOH/CH₂Cl₂, 8:92). LCMS m/z 499 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.19-6.78 (m, 8H, Ar—H), 4.64-4.42 (m, 4.6H, pip-H,dioxane-H, benzyl-H, CH_(OiPr)), 4.07 (m, 2H, dioxane-H), 3.76-3.68 (m,3.2H, dioxane-H, pip-H, benzyl-H), 3.49 (s, 1.2H, benzyl-H), 2.91-2.80(m, 2H, pip-H), 2.42-2.35 (m, 2H, NCH₂), 2.10-1.99 (m, 2.2H, dioxane-H,pip-H), 1.85-1.51 (m, 6H, pip-H, NCH₂CH₂), 1.31 (m, 7.8H, OCH(CH₃)₂,pip-H, dioxane-H). HPLC t_(R)=8.1 min.

IV.N-{1-[2-(1.3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzal)-2-phenylacetamide,oxalate (118AF77-109)

The desired compound was synthesized from 118AF52-95 (300 mg, 0.93 mmol)and phenylacetyl chloride (197 mg, 1.27 mmol) using the same method asfor preparation of 118AF66-102. Further purification by acidicion-exchange SPE cartridge was performed. Yield: 68 mg, 17%.

R_(f)=0.28 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 441 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.33-6.89 (m, 9H, Ar—H), 4.65-4.44 (m, 3.6H, pip-H,dioxane-H, benzyl-H), 4.09-4.03 (m, 2H, dioxane-H), 3.84 (s, 0.8H,benzyl-H), 3.76-3.67 (m, 2.4H, dioxane-H, pip-H), 3.57 (s, 1.2H,benzyl-H), 2.92-2.79 (m, 2H, pip-H), 2.44-2.34 (m, 2H, NCH₂), 2.10-1.98(m, 2.2H, dioxane-H, pip-H), 1.86-1.51 (m, 6H, pip-H, NCH₂CH₂),1.34-1.23 (m, 1.8H, pip-H, dioxane-H). HPLC t_(R)=6.1 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-fluoroethoxy)-phenyl]acetamide,oxalate (118AF85-113)

The desired compound was synthesized from 118AF52-95 (360 mg, 1.11 mmol)and 4-(2-fluoroethoxy)phenylacetyl chloride (282 mg, 1.30 mmol) usingthe same method as for preparation of 118AF66-102. Further purificationby acidic ion-exchange SPE cartridge was performed. Yield: 84 mg, 15%.

R_(f)=0.36 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 503 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.27-6.84 (m, 8H, Ar—H), 4.80 (m, 1H, OCH₂CH₂F),4.68 (m, 1H, OCH₂CH₂F), 4.65-4.45 (m, 3.6H, pip-H, dioxane-H, benzyl-H),4.22 (m, 1H, OCH₂CH₂F), 4.16 (m, 1H, OCH₂CH₂F), 4.10-4.03 (m, 2H,dioxane-H), 3.79-3.68 (m, 3.2H, dioxane-H, pip-H, benzyl-H), 3.51 (s,1.2H, benzyl-H), 2.92-2.82 (m, 2H, pip-H), 2.44-2.36 (m, 2H, NCH₂),2.12-1.99 (m, 2.2H, dioxane-H, pip-H), 1.88-1.51 (m, 6H, pip-H,NCH₂CH₂), 1.35-1.26 (m, 1.8H, pip-H, dioxane-H). HPLC t_(R)=7.0 min.

N-{1-[2-(5,5-Dimethyl-1,3dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate (118AF27-83)

The desired compound was synthesized fromN-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide103NLS63F (22 mg, 0.042 mmol) and 2,2-dimethyl-1,3-propandiol (33 mg,0.38 mmol) using the same method as for preparation of 130AF12-148.Purification of the product by reversed phase HPLC (C₁₈) afforded thetitle compound (2.8 mg, 12%). LCMS m/z 541 [M+H]⁺. HPLC t_(R)=9.9 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate (118AF29-84)

The desired compound was synthesized fromN-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide103NLS63F (38 mg, 0.074 mmol) and (R)-(−)-1,3-butandiol (33 mg, 0.38mmol) using the same method as for preparation of 130AF12-148.Purification of the product by reversed phase HPLC (C₁₈) afforded thetitle compound (11.6 mg, 28%). LCMS m/z 527 [M+H]⁺. HPLC t_(R)=8.7 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate (118AF31-85)

The desired compound was synthesized fromN-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide103NLS63F (40 mg, 0.078 mmol) and (S)-(+)-propylene glycol (30 mg, 0.39mmol) using the same method as for preparation of 130AF12-148.Purification of the product by reversed phase HPLC (C₁₈) afforded thetitle compound (21 mg, 53%). LCMS m/z 513 [M+H]⁺. HPLC t_(R)=9.9 min.

N-{1-[2-(4,6-Dimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate (118AF37-88)

The desired compound was synthesized fromN-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide103NLS63F (40 mg, 0.078 mmol) and 2,4-pentandiol (41 mg, 0.39 mmol)using the same method as for preparation of 130AF12-148. Purification ofthe product by reversed phase HPLC (C₁₈) afforded the title compound (9mg, 21%). LCMS m/z 541 [M+H]⁺. HPLC t_(R)=10.5 min.

N-(4-Fluorobenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamideoxalate (118AF87-114)

The desired compound was synthesized fromN-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxyphenyl)acetamide118AF58-98 (70 mg, 0.13 mmol) and (S)-(+)-propylene glycol (53 mg, 0.69mmol) using the same method as for preparation of 130AF12-148.Purification of the product by silica gel column chromatography, elutingwith a stepwise gradient of 0-4% methanol in dichloromethane, affordedthe title compound (31 mg, 46%). R_(f)=0.17 (MeOH/CH₂Cl₂ 4:96). LCMS m/z525 [M+H]⁺. ¹H NMR (CDCl₃, rotamers 0.4:0.6) δ 7.34-6.91 (m, 8H, Ar—H),5.03 & 4.92 (2t, 1H, J=4.8, dioxolane-H), 4.66-4.56 (m, 0.6H, pip-H),4.52 & 4.49 (2s, 2H, benzyl-H), 4.22-4.07 (m, 1.4H, dioxolane-H),3.95-3.89 (m, 0.6H, dioxolane-H), 3.84 (s, 0.8H, benzyl-H), 3.74-3.64(m, 0.4H, pip-H), 3.57 (s, 1.2H, benzyl-H), 3.40-3.33 (m, 1H,dioxolane-H), 2.78-2.86 (m, 2H, pip-H), 2.49-2.38 (m, 2H, NCH₂),2.10-2.01 (m, 1.2H, pip-H), 1.70-1.53 (m, 6H, pip-H, NCH₂CH₂), 1.40-1.22(m, 3.8H, pip-H, CH₃). HPLC t_(R)=8.7 mm.

N-(4-Fluorobenzyl)-2-(4-isopropylphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate (118AF91-117)

The desired compound was synthesized fromN-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropylphenyl)acetamide118AF63-100 (150 mg, 0.31 mmol) and (S)-(+)-propylene glycol (95 mg,1.24 mmol) using the same method as for preparation of 130AF12-148.Purification by silica gel column chromatography, eluting with astepwise gradient of 0-4% methanol in dichloromethane, afforded thetitle compound (51.2 mg, 34%).

R_(f)=0.19 (MeOH/CH₂Cl₂, 4:96). LCMS m/z 483 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.24-6.90 (m, 8H, Ar—H), 5.03 & 4.92 (2t, 1H, J=4.8,dioxolane-H), 4.67-4.55 (m, 0.6H, pip-H), 4.51 & 4.47 (2s, 2H,benzyl-H), 4.21-4.07 (m, 1.4H, dioxolane-H), 3.94-3.89 (m, 0.6H,dioxolane-H), 4.81-3.50 (m, 1.2H, benzyl-H, pip-H), 3.55 (s, 1.2H,benzyl-H), 3.40-3.33 (m, 1H, dioxolane-H), 2.94-2.83 (m, 3H, pip-H,CH(CH₃)₂), 2.47-2.38 (m, 2H, NCH₂), 2.09-2.01 (m, 1.2, pip-H), 1.86-1.52(m, 6H, pip-H, NCH₂CH₂), 1.31-1.19 (m, 9.8H, pip-H, CH₃, CH(CH₃)₂). HPLCt_(R)=8.6 min.

N-(4-Fluorobenzyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide,oxalate (118AF75-108)

The desired compound was synthesized fromN-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxyphenyl)acetamide118AF58-98 (70 mg, 0.13 mmol) and (R)-(−)-1,3-butandiol (60 mg, 0.66mmol) using the same method as for preparation of 130AF12-148.Purification of the product by silica gel column chromatography, elutingwith a stepwise gradient of 0-4% methanol in dichloromethane, affordedthe title compound (28 mg, 40%).

R_(f)=0.24 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 539 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.33-6.91 (m, 8H, Ar—H), 4.64-4.48 (m, 3.6H,benzyl-H, dioxane-H, pip-H), 4.04 (m, 1H, dioxane-H), 3.83 (s, 0.8H,benzyl-H), 3.75-3.63 (m, 2.4H, dioxane-H, pip-H), 3.56 (s, 1.2H,benzyl-H), 2.92-2.83 (m, 2H, pip-H), 2.44-2.38 (m, 2H, NCH₂), 2.09-2.01(m, 1.2 pip-H), 1.89-1.53 (m, 7H, dioxane-H, pip-H, NCH₂CH₂), 1.44-1.31(m, 1.8H, dioxane-H, pip-H), 1.19 (m, 3H, CH₃). HPLC t_(R)=9.0 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate (118AF33-86)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56(145 mg, 0.36 mmol) and 2-(2-bromoethyl)-2,5,5-trimethyl-1,3-dioxane(104.5 mg, 0.44 mmol) using the same method as for synthesis of130AF65-182. Purification of the product by silica gel columnchromatography, eluting with 5% methanol in dichloromethane, affordedthe title compound (119 mg, 58%).

R_(f)=0.15 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 555 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.20-6.79 (m, 8H, Ar—H), 4.66-4.56 (m, 0.6H, pip-H),4.49 & 4.43 (2s, 2H, benzyl-H), 3.76-3.68 (m, 3.2H, pip-H, benzyl-H,CH_(2OiBu)), 3.52-3.47 (m, 4H, dioxane-H), 3.41 (m, 1.2H, benzyl-H),2.93-2.84 (m, 2H, pip-H), 2.48-2.40 (m, 2H, NCH₂), 2.11-2.00 (m, 2.2H,CH_(OiBu), pip-H), 1.87-1.80 (m, 2.8H, pip-H, NCH₂CH₂), 1.72-1.50 (m,3.2H, pip-H), 1.33 (s, 3.8H, CH₃, pip-H), 1.02-0.87 (m, 12H, CH₃). HPLCt_(R)=9.8 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate (118AF35-87)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56 (311 mg, 0.78 mmol) and 2-(2-bromoethyl)-2-methyl-1,3-dioxolane(188 mg, 0.96 mmol) using the same method as for synthesis of130AF65-182. Purification by silica gel column chromatography, elutingwith 5% methanol in dichloromethane, afforded the title compound (61 mg,15%).

R_(f)=0.20 (MeOH/CH₂Cl₂, 5:95). LCMS m/z 513 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.17-6.76 (m, 8H, Ar—H), 4.64-4.52 (m, 0.6H, pip-H),4.47 & 4.41 (2s, 2H, benzyl-H), 3.93-3.82 (m, 4H, dioxolane-H),3.76-3.63 (m, 3.2H, benzyl-H, CH_(2OiBu), pip-H), 3.47 (s, 1.2H,benzyl-H), 2.94-2.83 (m, 2H, pip-H), 2.43-2.32 (m, 2H, NCH₂), 2.12-1.97(m, 2.2H, CH_(OiBu), pip-H), 1.84-1.72 (m, 2.8H, pip-H, NCH₂CH₂),1.70-1.50 (m, 3.2H, pip-H), 1.27 (s, 3.8H, CH₃, pip-H), 0.98 (m, 6H,CH_(3OiBu)). HPLC t_(R)=8.8 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(1,3-dioxolan-2-yl)propyl]piperidin-4-yl}acetamide,tartrate (118AF79-39)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56 (156 mg, 0.39 mmol) and 2-(3-chloropropyl)-1,3-dioxolane (62μL, 0.47 mmol) using the same method as for synthesis of 130AF65-182.Purification by silica gel column chromatography, eluting with astepwise gradient of 0-4% methanol in dichloromethane, afforded thetitle compound (49 mg, 25%).

R_(f)=0.45 (MeOH/CH₂Cl₂, 7:93). LCMS m/z 513 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.21-6.79 (m, 8H, Ar—H), 4.84 (t, 1H, J=4.4,dioxolane-H), 4.66-4.56 (m, 0.6H, pip-H), 4.50 & 4.44 (2s, 2H,benzyl-H), 3.95-3.90 (m, 2H, dioxolane-H), 3.84-3.67 (m, 5.2H, benzyl-H,CH_(2OiBu), pip-H, dioxolane-H), 3.50 (s, 1.2H, benzyl-H), 2.94-2.84 (m,2H, pip-H), 2.34-2.27 (m, 2H, NCH₂), 2.10-1.98 (m, 2.2H, CH_(OiBu),pip-H), 1.84-1.78 (m, 0.8H, pip-H), 1.71-1.50 (m, 7.2H, pip-H, NCH₂CH₂),1.34-1.25 (m, 0.8H, pip-H), 1.01 (m, 6H, CH_(3OiBu)). HPLC t_(R)=8.0min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-(3-piperidin-1-yl-propyl)piperidin-4-yl}-acetamide,dihydrochloride (98AF36-43)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56(189 mg, 0.47 mmol), 1-piperidine (61 μL, 0.61 mmol) and1-chloro-3-iodopropane (61 μL, 0.57 mmol) using the same method as forsynthesis of 130AF09-145. Purification of the product by silica gelcolumn chromatography, eluting with 10% methanol in dichloromethane,afforded the title compound (75.6 mg, 31%).

R_(f)=0.13 (MeOH/CH₂Cl₂, 1:4). LCMS m/z 524 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.21-6.81 (m, 8H, Ar—H), 4.66-4.54 (m, 0.6H, pip-H),4.51 & 4.45 (2s, 2H, benzyl-H), 3.78-3.68 (m, 3.2H, benzyl-H,CH_(2OiBu), pip-H), 3.52 (s, 1.2H, benzyl-H), 2.93-2.83 (m, 2H, pip-H),2.40-2.23 (m, 8H, NCH₂), 2.15-1.26 (m, 15H, pip-H, CH(CH₃)₂, CH₂), 1.02(m, 6H, CH(CH₃)₂). HPLC t_(R)=8.0 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-piperidin-4-yl}acetamide,oxalate (98AF41-44)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56 (185 mg, 0.46 mmol) and 2-(2-chloroethoxy)-tetrahydro-2H-pyran(75 μL, 0.51 mmol) using the same method as for synthesis of130AF09-145. Purification of the product by silica gel columnchromatography, eluting with 4.5% methanol in dichloromethane, affordedthe title compound (96 mg, 40%).

R_(f)=0.18 (MeOH/CH₂Cl₂, 4:96). LCMS m/z 527 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.21-6.78 (m, 8H, Ar—H), 4.67-4.56 (m, 0.6H, pip-H),4.54 (m, 1H, THP), 4.49 & 4.44 (2s, 2H, benzyl-H), 3.86-3.66 (m, 5.2H,benzyl-H, CH_(2OiBu), pip-H, CHO), 3.58-3.43 (m, 3.2H, benzyl-H, CHO),3.01-2.89 (m, 2H, pip-H), 2.62 & 2.55 (2t, 2H, J=6.0, NCH₂CH₂O),2.26-2.17 (m, 1.2H, pip-H), 2.12-1.96 (m, 1.8H, CH_(OiBu), pip-H),1.82-1.44 (m, 9.2H, pip-H, THP), 1.33-1.26 (m, 0.8H, pip-H), 1.01 (m,6H, CH(CH₃)₂). HPLC t_(R)=7.2 min.

N-(4-Fluorobenzal)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo--piperidin-1-yl)propyl]piperidin-4-yl}acetamide(98AF73-64)

Sodium hydride (60% suspension in oil, 26 mg, 0.65 mmol) was added to asolution of 2-piperidone (54 mg, 0.54 mmol) in dry THF (2 mL) underargon atmosphere. After 15 minutes stirring at rt the reaction mixturewas cooled to 0° C. over 15 minutes. A solution of1-bromo-3-chloropropane (160 μL, 1.62 mmol) was added dropwise to thecold mixture and stirring was continued overnight at rt. The mixture waspartitioned between water and ethyl acetate, the organic layer driedover sodium sulphate, filtered and evaporated to dryness. Purificationof the residue on silica gel column chromatography, eluting with astepwise gradient of 60-80% ethyl acetate in n-heptane, afforded1-(3-chloropropyl)-piperidin-2-one (33 mg, 35%).

R_(f)=0.22 (ethyl acetate/n-heptane 8:2). LCMS m/z 176 [M+H]⁺. HPLCt_(R)=1.8 min.

A solution of 1-(3-chloropropyl)-piperidin-2-one (32 mg, 0.18 mmol) indry DMF (2 mL) was added to a suspension of potassium carbonate (52 mg,0.38 mmol) andN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56 (62 mg, 0.15 mmol) in dry DMF (2 mL). After addition of sodiumiodide (25 mg, 0.17 mmol) the mixture was stirred overnight at 48° C.Afterwards it was partitioned between water and dichloromethane. Theorganic layer were dried over sodium sulphate, filtered and evaporatedto dryness. Purification of the residue by reversed phase HPLC (C₁₈)afforded the desired compound (2.6 mg, 3%).

R_(f)=0.11 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 538 [M+H]⁺. HPLC t_(R)=8.2 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-pyrrolidin-1-yl)propyl]piperidin-4-yl}acetamide,hydrochloride (98AF76-65)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56 (107 mg, 0.27 mmol), 2-pyrrolidone and 1-bromo-3-chloropropaneusing the same method as for synthesis of 98AF73-64. Purification of theproduct by silica gel column chromatography, eluting with a stepwisegradient of 4-8% methanol in dichloromethane, afforded the titlecompound (15 mg, 11%).

R_(f)=0.39 (MeOH/CH₂Cl₂ 1:9). LCMS m/z 524 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.20-6.80 (m, 8H), 4.65-4.53 (m, 0.6H), 4.50 & 4.44(2s, 2H), 3.76-3.67 (m, 3.2H), 3.51 (m, 1.2H), 3.34 (t, 2H, J=7.2), 3.26(t, 2H, J=7.2), 2.95-2.82 (m, 2H), 2.38-2.25 (m, 4H), 2.12-1.96 (m,4.2H), 1.86-1.56 (m, 6H), 1.29 (m, 0.8H), 1.01 (m, 6H). HPLC t_(R)=7.6min.

N-(4-Fluorobenzal)-2-(4-isobutoxyphenyl)-N-{1-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate (98AF 100-73)

Sodium hydride (55% suspension in oil, 144 mg, 3.31 mmol) was added to asolution of (R)-4-isopropyl-2-oxazolidinone (356 mg, 2.75 mmol) in drytetrahydrofuran (17 mL) under argon atmosphere. The suspension wasstirred for 1 hour at rt, then cooled to 0° C. and a solution of1-bromo-3-chloropropane in dry tetrahydrofuran (3 mL) was addeddropwise. After 48 h stirring at 58° C. the mixture was quenched withwater. The solvent was removed by evaporation under reduced pressure andthe residue partitioned between water and dichloromethane. The organiclayer was evaporated to dryness. Purification of the residue by silicagel column chromatography, eluting with a mixture of ethyl acetate andn-Heptane (70:30), afforded(4R)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one (401 mg, 71%).

A solution of (4R)-3-(3-chloropropyl)-4-isopropyloxazolidinon-2-one (160mg, 0.78 mmol) in dry DMF (2 mL) was added to a suspension of potassiumcarbonate (217 mg, 1.57 mmol) andN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)N-piperidin-4-yl-acetamide103NLS56 (250 mg, 0.63 mmol) in dry DMF (6 mL). After addition of sodiumiodide (113 mg, 0.75 mmol) the mixture was stirred overnight at 62° C.and partitioned between water and dichloromethane. The organic layerwere dried over sodium sulphate, filtered and evaporated to dryness.Purification of the residue by silica gel column chromatography, elutingwith 5% methanol in dichloromethane, afforded the desired compound (143mg, 40%).

R_(f)=0.28 (MeOH/CH₂Cl₂ 6:96). LCMS m/z 568 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.20-6.78 (m, 8H, Ar—H), 4.61-4.51 (m, 0.6H, pip-H),4.48 & 4.42 (2s, 2H, benzyl-H), 4.15 (t, 1H, J=8.8, oxa-H), 4.01 (m, 1H,oxa-H), 3.78-3.64 (m, 4.2H, pip-H, benzyl-H, oxa-H, CH_(2OiBu)), 3.48(m, 2.2H, benzyl-H, CONCHCH₂), 2.92-2.79 (m, 3H, pip-H, CONCHCH₂),2.34-2.22 (m, 2H, NCH₂CH₂CH₂), 2.10-1.96 (m, 3.2H, pip-H, CH_(iPr),CH_(OiBu)), 1.76-1.50 (m, 6H, pip-H, NCH₂CH₂), 1.32-1.26 (m, 0.8H,pip-H), 0.99 (m, 6H, CH_(3OiBu)), 0.81-0.87 (m, 6H, CH_(3iPr)). HPLCt_(R)=9.1 min.

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate (98AF94-71)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56 (298 mg, 0.75 mmol), 2-oxazolidoneand 1-bromo-3-chloropropaneusing the same method as for synthesis of 98AF100-73. Purification ofthe product by silica gel column chromatography, eluting with 5%methanol in dichloromethane, afforded the title compound (157 mg, 40%).

R_(f)=0.23 (MeOH/CH₂Cl₂ 5:95). LCMS m/z 526 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.20-6.78 (m, 8H, Ar—H), 4.61-4.50 (m, 0.6H, pip-H),4.48 & 4.42 (2s, 2H, benzyl-H), 4.29-4-24 (m, 2H, oxa-OCH₂), 3.78-3.65(m, 3.2H, pip-H, benzyl-H, CH_(2OiBu)), 3.52-3.48 (m, 3.2H, benzyl-H,oxa-NCH₂), 3.25 (t, 2H, J=7.2, CONCH₂CH₂CH₂N), 2.89-2.80 (m, 2H, pip-H),2.33-2.26 (m, 2H, NCH₂CH₂CH₂NCO), 2.09-1.76 (m, 3H, pip-H, CH_(OiBu)),1.71-1.49 (m, 5.2H, pip-H, NCH₂CH₂CH₂), 1.33-1.27 (m, 0.8H, pip-H), 1.00(m, 6H, CH_(3OiBu)). HPLC t_(R)=7.8 min.

(S)-4-Methyl-oxazolidin-2-one (118AF10-77)

Triethylamine (0.94 mL, 6.65 mmol) was added dropwise to a solution ofL-alaninol (500 mg, 6.65 mmol) and 1,1-carbonyldiimidazole (1.29 g, 7.98mmol) in dry THF (10 mL) at rt, under argon atmosphere. The reactionmixture was stirred overnight at 60° C. The solvent was removed byevaporation under reduced pressure. Purification of the residue bysilica gel column chromatography, eluting with 6% methanol indichloromethane, afforded the desired compound (450 mg, 67%).

R_(f)=0.39 (MeOH/CH₂Cl₂ 6:94). ¹H NMR (CDCl₃) δ 6.74 (m, 1H), 4.45-4.34(m, 1H), 4.98-4.77 (m, 2H), 1.17 (m, 3H).

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-methyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,tartrate (118AFI18-81)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56 (205 mg, 0.52 mmol), (S)-4-methyl-oxazolidin-2-one (118AF10-77)and 1-bromo-3-chloropropane using the same method as for synthesis of98AF100-73. Further purification by acidic ion-exchange SPE cartridgewas performed. Yield: 106 mg, 38%.

R_(f)=0.22 (MeOH/CH₂Cl₂ 6:94). LCMS m/z 540 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.20-6.78 (m, 8H, Ar—H), 4.61-4.50 (m, 0.6H, pip-H),4.48 & 4.42 (2s, 2H, benzyl-H), 4.34 (m, 1H, oxa-H), 3.84-3.66 (m, 5.2H,pip-H, benzyl-H, oxa-H, CH_(2OiBu)), 3.49 (s, 1.2H, benzyl-H), 3.42-3.34(m, 1H, CONCH₂), 3.09-3.00 (m, 1H, CONCH₂), 2.92-2.79 (m, 2H, pip-H),2.33-2.26 (m, 2H, NCH₂), 2.10-1.98 (m, 2.2H, pip-H, CH_(OiBu)),1.86-1.76 (m, 0.8H, pip-H), 1.72-1.48 (m, 5.2H, pip-H, NCH₂CH₂), 1.29(m, 0.8H, pip-H), 1.22 (m, 3H, oxa-CH₃), 0.99 (m, 6H, CH_(3OiBu)). HPLCt_(R)=8.4 min.

V.

(S)-4-Ethyl-oxazolidin-2-one (118AF08-76)

Triethylamine (0.80 mL, 5.74 mmol) was added dropwise to a solution of(S)-(+)-2-amino-1-butanol (515 mg, 5.77 mmol) and1,1-carbonyldiimidazole (1.10 g, 6.78 mmol) in dry THF (10 mL) at rtunder argon atmosphere. The reaction mixture was stirred overnight atrt. The solvent was removed by evaporation under reduced pressure.Purification of the residue by silica gel column chromatography, elutingwith 6% methanol in dichloromethane, afforded the desired compound (485mg, 73%). R_(f)=0.42 (MeOH/CH₂Cl_(2 6:94)).

N-(4-Fluorobenzal)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-ethyl-2-oxo-oxazolidin-3-yl)-propyl]piperidin-4-yl}acetamide,oxalate (118AF16-80)

The desired compound was synthesized fromN-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)-N-piperidin-4-yl-acetamide103NLS56 (202 mg, 0.51 mmol), (S)-4-ethyl-oxazolidin-2-one (118AF08-76)and 1-bromo-3-chloropropane using the same method as for synthesis of98AF100-73. Purification of the product by acidic ion-exchange SPEcartridge afforded the title compound (126 mg, 44%).

R_(f)=0.28 (MeOH/CH₂Cl₂ 6:94). LCMS m/z 554 [M+H]⁺. ¹H NMR (CDCl₃,rotamers 0.4:0.6) δ 7.20-6.78 (m, 8H, Ar—H), 4.61-4.52 (m, 0.6H, pip-H),4.48 & 4.42 (2s, 2H, benzyl-H), 4.32-4.26 (m, 1H, oxa-H), 3.94-3.88 (m,1H, oxa-H), 3.76-3.66 (m, 4.2H, pip-H, benzyl-H, oxa-H, CH_(2OiBu)),3.49 (s, 1.2H, benzyl-H), 3.46-3.37 (m, 1H, CONCH₂), 3.04-2.96 (m, 1H,CONCH₂), 2.90-2.78 (m, 2H, pip-H), 2.33-2.24 (m, 2H, NCH₂), 2.11-1.96(m, 2.2H, pip-H, CH_(OiBu)), 1.82-1.75 (m, 0.8H, pip-H), 1.74-1.42 (m,7.2H, pip-H, NCH₂CH₂, CH₂CH₃), 1.29 (m, 0.8H, pip-H), 1.00 (m, 6H,CH_(3OiBu)), 0.85 (m, 3H, CH₂CH₃). HPLC t_(R)=8.7 min.

2-(2-Bromoethyl)-1,3-oxothiolane (121JP11)

Adapting a procedure by Yamada et al (Tetrahedron Lett., 1998, 39,7709-7712), boron trifluoride ether complex (5 mL, 40 mmol) was addeddropwise to a mixture of 2-(2-bromoethyl)-1,3-dioxolane (1.45 g, 8.0mmol) and 2-mercaptoethanol (2.81 mL, 40 mmol) in dichloromethane (15mL) at rt under Ar atmosphere and stirred at rt overnight. Sat. aq.NaHCO₃ (100 mL) was added to the crude mixture, followed by extractionusing Et₂O (3×100 mL), drying (Na₂SO₄) and evaporation in vacuo.Purification by Kugelrohr distillation (90° C., 1.0 mmHg) afforded 1.08g of the title compound as a yellow oil. The purity of this materialafter distillation was 71% (determined by GC analysis) and it was usedas such in the alkylation step (121JP12).

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1,3-oxothiolan-2-yl)ethyl]piperidin-4-yl}acetamide,L-tartrate (121JP12)

The title compound was prepared by the general procedure described abovefor 103NLS63-F using 103NLS56 (130 mg, 0.33 mmol) and 121JP11 (85 mg,0.43 mmol) as the alkylating agent. Workup as in 121JP11 followed byvacuum filtration chromatography over silica gel (VFC, ethylacetate/n-heptane 0:1→ethyl acetate/n-heptane 1:0→ethyl acetate/MeOH4:1) gave 85 mg (51%) of 121JP12 as colourless thick oil. The L-tartratesalt was prepared as described above.

R_(f)=0.57 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 515 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.5:0.5) δ 7.20-6.76 (m, 8H), 5.10-5.00 (m, 1H, oxothiolane-H),4.66-4.54 (m, 0.5H, pip-H), 4.48 and 4.42 (2s, 2H, benzyl-H), 4.30-4.22(m, 1H, oxothiolane-H), 3.78-3.64 (m, 4.5H, pip-H, benzyl-H,oxothiolane-H, OCH_(2OiBu)), 3.48 (s, 1H, benzyl-H), 3.01-2.82 (m, 4H,pip-H, oxothiolane-H), 2.60-2.34 (m, 2H, NCH₂), 2.21-1.56 (m, 8H, pip-H,NCH₂CH₂, CH_(OiBu)), 1.32-1.22 (m, 1H, pip-H), 1.04-0.96 (m, 6H,CH_(3OiBu). HPLC t_(R)=10.1 mm.

2-(4-Bromophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-acetamide,L-tartrate (121JP13)

The title compound was prepared by the procedure described above for117NLS87-A using 118AF52-95 (200 mg, 0.62 mmol) and 4-bromophenylaceticacid (500 mg, 2.32 mmol). Sat. aq. NaHCO₃ (100 mL) was added to thecrude mixture, followed by extraction using CH₂Cl₂ (3×100 mL), drying(Na₂SO₄) and evaporation in vacuo. VFC over silica gel (ethylacetate/n-heptane 1:1→ethyl acetate/n-heptane 1:0→ethyl acetate/MeOH2:1) gave 250 mg (78 %) of 121JP12 as a thick oil. The L-tartrate saltwas prepared as described above.

R_(f)=0.49 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 521 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.50-6.88 (m, 8H), 4.62-4.57 (m, 0.4H, pip-H), 4.50(t, 1H, J=4.9, dioxane-H) 4.48 and 4.42 (2s, 2H, benzyl-H), 4.06-4.00(m, 2H, dioxane-H), 3.76 and 3.50 (2s, 2H, benzyl-H), 3.75-3.60 (m,2.6H, pip-H, dioxane-H), 3.01 and 2.90 (2d, 2H, J=10.5, pip-H), 2.52 and2.41 (2t, 2H, J=8.0, NCH₂), 2.10-1.98 (m, 2.2 H, dioxane-H, pip-H),1.97-1.58 (m, 6H, pip-H, NCH₂CH₂), 1.38-1.20 (m, 1.8H, dioxane-H,pip-H). HPLC t_(R)=8.3 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutylamino-phenyl)acetamide,L-tartrate (121 JP27)

Adapting a protocol by Buchwald et al (J. Am. Chem. Soc., 1996, 118,7215-7216), 121JP13 (100 mg, 192 μmol), isobutylamine (17 mg, 230 μmol),Pd₂dba₃ (11.6 mg, 19.2 μmol), BINAP (12.0 mg, 38.4 μmol) and NaOtBu(25.8 mg, 269 μmol) were weighed into a flask, toluene (2 mL) was addedand the resulting mixture was stirred at 80° C. for 18 h. Workup as in121JP13 followed by preparative reversed-phase (C₁₈) HPLC afforded 25.7mg (27.0%) of 121JP27 as a thick colourless oil. The L-tartrate salt wasprepared as described above.

R_(f)=0.30 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 512 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.5:0.5) δ 7.10-6.81 (m, 6H), 6.59-6.49 (m, 2H), 4.65-4.55 (m,0.5H, pip-H), 4.55-4.50 (m, 1H, dioxane-H), 4.50 and 4.43 (2s, 2H,benzyl-H), 4.10-4.02 (m, 2H, dioxane-H), 3.80-3.67 (m, 3.5H, pip-H,benzyl-H, dioxane-H) 3.45 (s, 1H, benzyl-H), 2.95-2.85 (m, 4H, pip-H,NHCH₂CH(CH₃)₂)), 2.45-2.35 (m, 2H, NCH₂), 2.09-1.99 (m, 2H, dioxane-H,pip-H), 1.91-1.50 (m, 7H, NCH₂CH₂, pip-H, NHCH₂CH(CH₃)₂), 1.38-1.25 (m,2H, dioxane-H, pip-H), 0.98 (m, 6H, NHCH₂CH(CH₃)₂). HPLC t_(R)=8.2 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propylamino-phenyl)acetamide,L-tartrate (121 JP28)

Prepared identically as described in the protocol for the synthesis of121JP27, using propylamine (16 mg, 230 μmol) instead of isobutylamine toafford 24 mg (25%) of 121JP28 as a thick oil. The L-tartrate salt wasprepared as described above.

R_(f)=0.33 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 498 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.5:0.5) δ 7.11-6.82 (m, 6H), 6.53-6.43 (m, 2H), 4.58-4.49 (m,0.5H, pip-H), 4.48-4.45 (m, 1H, dioxane-H), 4.42 and 4.35 (2s, 2H,benzyl-H), 4.05-3.95 (m, 2H, dioxane-H), 3.70-3.60 (m, 3.5H, pip-H,benzyl-H, dioxane-H), 3.40 (s, 1H, benzyl-H), 3.05-2.95 (m, 2H, pip-H),2.85-2.70 (m, 2H, NHCH₂CH₂CH₃), 2.48-2.38 (m, 2H, NCH₂), 2.05-1.90 (m,2H, dioxane-H, pip-H), 1.92-1.40 (m, 8H, NCH₂CH₂, pip-H, NHCH₂CH₂CH₃),1.40-1.28 (m, 2H, dioxane-H, pip-H), 0.98 (m, 3H, NHCH₂CH₂CH₃). HPLCt_(R)=7.3 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-(1-nitropropyl)-phenyl)acetamide,L-tartrate (121JP34)

Adapting a protocol by Vogl & Buchwald (J. Org. Chem., 2002, 67,106-111), 121JP13 (135 mg, 0.26 mmol), 1-nitropropane (47 mg, 0.52mmol), Cs₂CO₃ (95 mg, 0.29 mmol), 2-di-tert-butylphosphinobiphenyl (15.5mg, 52 μmol) and Pd₂dba₃ (11.9 mg, 13 μmol) were weighed into a flask,DME (2 mL) was added and the reaction was stirred at 60° C. for 20 h.Workup as in 121JP13 followed by preparative TLC (CH₂Cl₂/MeOH, 15:1, 10×eluted) afforded 22 mg (16%) of 121JP34 as a thick colourless oil. TheL-tartrate salt of the title compound was prepared as described above.

R_(f)=0.58 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 528 [M+H]⁺. HPLC t_(R)=8.1 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-oxopyrrolidin-1-yl)phenyl)acetamideL-tartrate (121JP31)

Adapting a protocol by Yin & Buchwald (J. Am. Chem. Soc., 2002, 124,6043-6048), 121JP13 (124 mg, 0.24 mmol), pyrrolidone (24.7 mg, 0.29mmol), Cs₂CO₃ (111 mg, 0.34 mmol), Xantphos (20.8 mg, 0.036 mmol) andPd₂dba₃ (11.0 mg, 0.012 mmol) were weighed into a flask, dioxane (2 mL)was added and the reaction was stirred at 90° C. for 70 h. Workup as in121JP13 and purification as in 121JP27 afforded 8 mg (7%) of 121JP31 asa thick colourless oil. The L-tartrate salt was prepared as describedabove.

R_(f)=0.31 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 524 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.60-6.80 (m, 8H), 4.60-4.50 (m, 0.4H, pip-H), 4.47(t, 1H, J=5.1, dioxane-H) 4.42 and 4.38 (2s, 2H, benzyl-H), 4.04-3.97(m, 2H, dioxane-H), 3.82-3.60 (m, 5.4H, pip-H, dioxane-H, benzyl-H,pyrrol-H), 3.25 (s, 1.2H, benzyl-H), 2.90-2.72 (m, 2H, pip-H), 2.60-2.50(m, 2H, pyrrol-H), 2.39-2.32 (m, 2H, NCH₂) 2.18-1.90 (m, 4.2 H,dioxane-H, pip-H, pyrrol-H), 1.81-1.40 (m, 6H, pip-H, NCH₂CH₂),1.32-1.18 (m, 1.8H, dioxane-H, pip-H). HPLC t_(R)=4.9 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutylsulfanyl-phenyl)acetamideL-tartrate (121JP33)

Adapting a protocol by Li (J. Org. Chem., 2002, 67, 3643-3650), 121JP13(120 mg, 0.231 mmol), 2-methyl-1-propanethiol (25 mg, 0.28 mmol),[(t-Bu)₂P(OH)]₂PdCl₂ (11.6 mg, 0.0231 mmol) and NaOtBu (44 mg, 0.46mmol) were weighed into a flask, toluene (2 mL) was added and thereaction was stirred at 110° C. for 16 h. Workup as in 121JP13 andpurification as in 121JP27 afforded 1.7 mg (1.4%) of 121JP33 as a thickcolourless oil. The L-tartrate salt of the title compound was preparedas described above.

R_(f)=0.46 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 529 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.24-6.82 (m, 8H), 4.57-4.48 (m, 0.4H, pip-H), 4.47(t, 1H, J=5.1, dioxane-H), 4.45 and 4.38 (2s, 2H, benzyl-H), 4.05-3.95(m, 2H, dioxane-H), 3.72 (s, 0.8 H, benzyl-H), 3.70-3.60 (m, 2.6H,pip-H, dioxane-H) 3.44 (s, 1.2H, benzyl-H), 2.87-2.75 (m, 2H, pip-H),2.72 (t, 2H, J=6.5, SCH₂CH(CH₃)₂)), 2.38-2.28 (m, 2H, NCH₂), 2.05-1.88(m, 2.2H, dioxane-H, pip-H), 1.81-1.48 (m, 7H, NCH₂CH₂, pip-H,SCH₂CH(CH₃)₂), 1.30-1.20 (m, 1.8H, dioxane-H, pip-H), 0.98 (t, 6H,J=6.7, SCH₂CH(CH₃)₂). HPLC t_(R)=8.8 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iodophenyl)-acetamide,L-tartrate (121JP40)

The title compound was prepared by the procedure described above117NLS87-A using 118AF52-95 (400 mg, 1.24 mmol) and 4-iodophenylaceticacid (1.22 g, 4.64 mmol). Workup as in 121JP13 and purification as in121JP34 gave 320 mg (46%) of 121JP40 as a colourless thick oil. TheL-tartrate salt was prepared as described above.

R_(f)=0.52 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 567 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.65-7.55 (m, 2H), 7.16-6.85 (m, 6H), 4.59-4.50 (m,0.6H, pip-H), 4.51 (t, 1H, J=5.0, dioxane-H), 4.50 and 4.42 (2s, 2H,benzyl-H), 4.09-4.00 (m, 2H, dioxane-H), 3.75 and 3.49 (2s, 2H,benzyl-H), 3.74-3.54 (m, 2.4 H, pip-H, dioxane-H), 2.85 (d, 2H, J=10.6,pip-H), 2.41-2.35 (m, 2H, NCH₂), 2.08-1.95 (m, 2.2H, dioxane-H, pip-H),1.88-1.50 (m, 6H, pip-H, NCH₂CH₂), 1.39-1.27 (m, 1.8H, dioxane-H,pip-H). HPLC t_(R)=8.6 min.

2-(4-Acetophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-acetamide,L-tartrate (121JP44).

Adapting a protocol by Cacchi et al (Org. Lett, 2003, 5, 289-293),121JP40 (68 mg, 0.12 mmol), acetic anhydride (61 mg, 0.6 mmol), Pd₂dba₃(1.4 mg, 1.5 μmol), lithium chloride (26 mg, 0.6 mmol) and EtNiPr₂ (31mg, 0.24 mmol) were weighed into a flask, DMF (0.9 mL) was added and theresulting mixture was stirred at 100° C. for 18 h. Workup as in 121JP13and purification as in 121JP34 afforded 19 mg (33%) of 121JP44 as athick colourless oil. The L-tartrate salt was prepared as describedabove.

R_(f)=0.50 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 483 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) 7.88-7.78 (m, 2H), 7.36-6.84 (m, 6H), 4.58-4.49 (m,0.4H, pip-H), 4.48-4.46 (m, 1H, dioxane-H), 4.45 and 4.38 (2s, 2H,benzyl-H), 4.05-3.95 (m, 2H, dioxane-H), 3.81 and 3.55 (2s, 2H,benzyl-H), 3.70-3.60 (m, 2.6H, pip-H, dioxane-H) 2.85-2.75 (m, 2H,pip-H), 2.54 and 2.52 (2s, 3H, CH₃), 2.38-2.27 (m, 2H, NCH₂), 2.05-1.92(m, 2.2H, dioxane-H, pip-H), 1.81-1.45 (m, 6H, NCH₂CH₂, pip-H),1.32-1.22 (m, 1.8H, dioxane-H, pip-H). HPLC t_(R)=5.5 min.

2-[4-(1-Hydroxyiminoethyl)phenyl]-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,L-tartrate (121JP48)

121JP44 (14 mg, 29 μmol), pyridine (4.6 mg, 58 μmol) and ethanol (5 mL)were placed in a flask, to which hydroxylamine hydrochloride (4.1 mg, 58μmol) was added and the resulting mixture was stirred at rt for 5 h.Workup as in 121JP13 and purification as in 121JP34 afforded 7 mg (49%)of 121JP48 as a thick colourless oil. The L-tartrate salt was preparedas described above.

R_(f)=0.40 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 498 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) 7.63-7.51 (m, 2H), 7.33-6.88 (m, 6H), 4.66-4.58 (m,0.4H, pip-H), 4.56-4.53 (m, 1H, dioxane-H), 4.51 and 4.40 (2s, 2H,benzyl-H), 4.10-4.04 (m, 2H, dioxane-H), 3.85 and 3.58 (2s, 2H,benzyl-H), 3.78-3.67 (m, 2.6H, pip-H, dioxane-H) 2.97-2.83 (m, 2H,pip-H), 2.47-2.37 (m, 2H, NCH₂), 2.26 and 2.24 (2s, 3H, CH₃), 2.12-1.98(m, 2.2H, dioxane-H, pip-H), 1.88-1.58 (m, 6H, NCH₂CH₂, pip-H),1.37-1.29 (m, 1.8H, dioxane-H, pip-H). HPLC t_(R)=4.0 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-morpholin-4-yl-phenyl)acetamide,L-tartrate (121JP49)

Adapting a protocol by Buchwald et al (Org Lett., 2002, 4, 581-584),121JP40 (50 mg, 88 μmol), morpholine (9.2 mg, 106 μmol), CuI (1.7 mg,8.8 μmol) and K₃PO₄ (37.6 mg, 177 μmol) were weighed into a flask in airatmosphere, ethylene glycol (2 mL) was added and the resulting mixturewas stirred at 80° C. for 16 h under air atmosphere. Workup as in121JP13 and purification as in 121JP34 afforded 4.7 mg (10%) of 121JP49as a thick colourless oil. The L-tartrate salt was prepared as describedabove.

R_(f)=0.33 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 526 [M+H]⁺.¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.18-6.72 (m, 8H), 4.62 and 4.37 (2s, 2H, benzyl-H),4.57-4.50 (m, 0.4H, pip-H), 4.50-4.42 (m, 1H, dioxane-H), 4.05-3.95 (m,2H, dioxane-H), 3.82-3.75 (m, 4H, morph-H), 3.69 and 3.43 (2s, 2H,benzyl-H), 3.68-3.61 (m, 2.6H, pip-H, dioxane-H), 3.12-3.03 (m, 4H,morph-H), 2.85-2.75 (m, 2H, pip-H), 2.38-2.27 (m, 2H, NCH₂), 2.07-1.90(m, 2.2H, dioxane-H, pip-H), 1.82-1.45 (m, 6H, NCH₂CH₂, pip-H),1.30-1.22 (m, 1.8H, dioxane-H, pip-H). HPLC t_(R)=6.2 min.

N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyrazol-1-yl-phenyl)acetamide,L-tartrate (121JP56)

Adapting a protocol by Buchwald et al (J. Am. Chem. Soc., 2001, 123,7727-7729), 121JP40 (48 mg, 85 μmol), pyrazole (7 mg, 102 μmol), CuI(0.4 mg, 1.7 μmol), racemic trans-1,2-cyclohexanediamine (1.0 mg, 8.5μmol), and K₂CO₃ (25 mg, 181 μmol) were weighed into a flask, dioxane(1.5 mL) was added and the resulting mixture was stirred at 110° C. for60 h. Workup as in 121JP13 and purification as in 121JP34 afforded 3.9mg (9%) of 121JP56 as a thick colourless oil. The L-tartrate salt wasprepared as described above.

R_(f)=0.27 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 507 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.6:0.4) δ 7.86 and 7.82 (2d, 1H, J=2.2, pyraz-H), 7.64 (d, 1H,J=4.4, pyraz-H), 7.62-6.83 (m, 8H), 6.42-6.36 (m, 1H, pyraz-H),4.60-4.49 (m, 0.6H, pip-H), 4.48 (t, 1H, J=5.1, dioxane-H), 4.45 and4.38 (2s, 2H, benzyl-H), 4.05-3.95 (m, 2H, dioxane-H), 3.80 and 3.54(2s, 2H, benzyl-H), 3.70-3.61 (m, 2.4H, pip-H, dioxane-H) 2.85-2.75 (m,2H, pip-H), 2.38-2.28 (m, 2H, NCH₂), 2.07-1.90 (m, 2.2H, dioxane-H,pip-H), 1.82-1.45 (m, 6H, NCH₂CH₂, pip-H), 1.35-1.22 (m, 1.8H,dioxane-H, pip-H). HPLC t_(R)=6.4 min.

2-(2-Bromopropyl)-1,3-dioxane (121 JP80)

Adapting a procedure of Büchi and Wüest (J. Org. Chem, 1969, 34,1122-1123), crotonaldehyde (3 g, 43 mmol) was added dropwise to conc.aq. HBr (5.2 g, 64 mmol) over 5 min at 5° C. under air atmosphere. After15 min of stirring at 5° C., during which time the mixture changed fromcolourless to brownish, 1,3-propanediol (8.1 g, 107 mmol) was added andthe reaction was stirred at 5° C. for further 0.5 h before allowing itwarm to rt, and finally stirring it at rt for 2 h. The crude reactionmixture was then n-heptane extracted (2×200 mL), the combined n-heptaneextracts were Na₂SO₄ dried, evaporated in vacuo and 121JP80 was isolatedby Kugelrohr distillation (75° C., 0.18 mmHg) to obtain 124 mg (1.4%) ofthe title compound as a colourless liquid.

Characterization Data: ¹H-NMR (CDCl₃) δ 4.73 (dd, 1H, J=7.2, 3.4),4.26-4.18 (m, 1H), 4.15-4.06 (m, 2H), 3.83-3.75 (m, 2H), 2.15-1.97 (m,3H), 1.71 (d, 3H, J=6.6), 1.38-1.32 (m, 1H).

N-{1-[2-(1,3-Dioxan-2-yl)-1-methylethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iso-butoxyphenyl-acetamide,L-tartrate (121JP84)

The title compound was prepared by the procedure described above103NLS63-F using 103NLS56 (202 mg, 0.51 mmol) and 121JP80 (124 mg, 0.59mmol) as the alkylating agent. Workup as in 121JP13 and purification asin 121JP34 gave 1.9 mg (0.7%) of 121JP84 as a thick oil. The L-tartratesalt was prepared as described above.

R_(f)=0.43 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 527 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.5:0.5) δ 7.19-6.80 (m, 8H), 4.50-4.33 (m, 3.5H, dioxane-H,benzyl-H, pip-H), 4.04-3.93 (m, 2H, dioxane-H), 3.72-3.55 (m, 5.5H,dioxane-H, benzyl-H, pip-H, OCH_(2OiBu)), 3.42 (s, 1H, benzyl-H),2.78-2.59 (m, 2H, pip-H), 2.34-2.16 (m, 1H, NCH), 2.08-1.89 (m, 2H,pip-H, CH_(OiBu)), 1.79-0.77 (m, 17H, CH₃ _(OiBu), NCHCH₃, NCHCH₂,pip-H, dioxane-H). HPLC t_(R)=8.5 min.

4-Iodophenylacetic acid ethyl ester (121JP58) .

4-Iodophenylacetic acid (3 g), ethanol (20 mL) and conc. H₂SO₄ (5 mL)were refluxed overnight. Ca. 15 mL ethanol was then evaporated, theresidue was extracted with dichloromethane (3×100 mL), the combinedorganic extracts were washed with sat. aq. NaHCO₃, dried over Na₂SO₄ andevaporated in vacuo to afford 2.97 g (90%) of 121JP58 as a yellow oil.

Characterization Data: ¹H-NMR (CDCl₃) δ 7.62 (d, 2H, J=8.4), 7.02 (d,2H, J=8.4), 4.07 (q, 2 H, J=7.0), 3.59 (s, 2H), 1.12 (t, 3H, J=7.0).

4-Pyrazol-1-ylphenylacetic acid ethyl ester (121JP64)

121JP58 (290 mg, 1.0 mmol) was treated identically as 121JP40 for thesynthesis of 121JP56. After heating the reaction to 110° C. for 72 h andworkup as in 121JP13, the crude mixture was purified by VFC (CH₂Cl₂/MeOH1:0-20:1) to furnish 180 mg (78 %) of 121JP64 as a yellow oil.

Characterization Data: ¹H-NMR (CDCl₃) δ 7.92 (dd, 1H, J=2.3, 1.0), 7.72(d, 1H, J=1.3), 7.62 (d, 2H, J=8.7), 7.39 (d, 2H, J=8.7), 6.42 (dd, 1H,J=2.5, 1.9), 4.18 (q, 2 H, J=7.0), 3.61 (s, 2H), 1.22 (t, 3H,J=7.1).

4-Pyrazol-1-ylphenylacetic acid (121JP68, 87)

121JP64 (180 mg, 0.78 mmol), lithium hydroxide monohydrate (164 mg, 3.9mmol), H₂O (10 mL) and THF (10 mL) were stirred overnight at rt. Thecrude mixture was then extracted with dichloromethane (3×150 mL), the pHof the aqueous phase was adjusted to ca. pH 3 using 4M HCl and extractedwith dichloromethane (3×150 mL). The combined organic layers were driedover Na₂SO₄, filtered and evaporated in vacuo to provide 128 mg (81%) of121JP68 as a yellow solid.

Characterization Data: ¹H-NMR (CDCl₃) δ 7.90 (m, 1H), 7.75 (m, 1H), 7.63(d, 2H, J=8.6), 7.38 (d, 2H, J=8.6), 6.45 (m, 1H), 3.68 (s, 2H).

N-{1-[2-(1,3-Dioxan-4-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyrazol-1-yl-phenyl)acetamideL-tartrate (121JP91)

The title compound was prepared by the general procedure described above117NLS87-A using 128NLS52 (87 mg, 0.27 mmol) and 121JP87 (60 mg, 0.27mmol). Workup as in 121JP13 and purification as in 121JP34 gave 25 mg(18%) of 121JP91 as a colourless oil. The L-tartrate salt was preparedas described above.

R_(f)=0.34 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 507 [M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.5:0.5) δ 7.92 and 7.88 (2d, 1H, J=2.2, pyraz-H), 7.71 (d, 1H,J=4.7, pyraz-H), 7.69-6.90 (m, 8H), 6.48-6.42 (m, 1H, pyraz-H), 5.00 (d,1H, J=6.3, dioxane-H), 4.65 (d, 1H, J=6.4, dioxane-H), 4.63-4.55 (m,0.5H, pip-H), 4.52 and 4.46 (2s, 2H, benzyl-H), 4.10-4.02 (m, 1H,dioxane-H), 3.86 and 3.57 (2s, 2H, benzyl-H), 3.78-3.55 (m, 2.5H, pip-H,dioxane-H) 2.93-2.82 (m, 2H, pip-H), 2.49-2.30 (m, 2H, NCH₂), 2.10-1.98(m, 1H, pip-H), 1.90-1.33 (m, 9H, NCH₂CH₂, pip-H, dioxane-H). HPLCt_(R)=5.2 min.

N-[1-((R)-3,5-Dihydroxypentyl)piperidine-4-yl]-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate (130AF93-189)

The desired compound was synthesized from(S)-5-[(4-methylbenzenesulfonyl)oxy]pentane-1,3-diol (Moune et al, J.Org. Chem., 1997, 62, 3332-3339) and 103NLS56 using the same method asdescribed for the preparation of 130AF65-182.

R_(f)=0.48 (MeOH/CH₂Cl₂, 10:90). LCMS m/z 501 [M+H]⁺. HPLC t_(R)=7.4min.

N-{1-[2-((4R)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate (130AF95-190)

The desired compound (7.9 mg, 55%) was synthesized from 130AF93-189(18.6 mg, 0.028 mmol) using the same method as for the synthesis of130AF67-183. The enantiomeric excess was determined to be 99% usingchiral HPLC analysis (Chiralpak AD column, 4.6×250 mm; heptane/I—PrOH50:50, 0.3% DEA; 0.5 mL/min; t_(R) 22.7 min). The ¹H NMR and LCMS datawere identical with 130AF67-183.

1-(1,2,4-Triazol-4-yl)phenylacetic acid (141JP01)

Adapting a protocol by Catarzi et al (J. Med Chem., 2001, 44,3157-3165), diformylhydrazine (352 mg, 4.0 mmol) and then dropwisetrimethylsilyl chloride (2.53 mL, 20 mmol) and Et₃N (1.30 mL, 9.3 mmol)were added to a suspension of 4-aminophenylacetic acid (201 mg, 1.33mmol) in anhydrous pyridine. The mixture was heated at 100° C.overnight, volatiles were removed at reduced pressure and the resultingsolid was treated with water (6 mL), collected, washed with H₂O anddried in vacuo to provide 251 mg (93%) of 141JP01 as a light brownsolid. LCMS m/z 204[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 9.05 (s, 2H), 7.62 (d, 1H,J=8.6), 7.40 (d, 1H, J=8.2), 3.61 (s, 2H).

N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4(1,2,4-triazol-4-yl)phenyl]acetamide,L-tartrate (141JP13)

The acid 141JP01 (35 mg, 0.17 mmol),N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)amine(118AF52-95, 55 mg, 0.17 mmol) and diisopropylethylamine (52 mg, 0.51mmol) were dissolved in DMF (5 mL). Bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBroP, 119 mg, 0.25 mmol) was added, and themixture was stirred at rt for 2 h. The mixture was concentrated andpassed onto an acidic ion exchange SPE cartridge. The cartridge waswashed with methanol (8×4 mL) and the remaining product was eluted offthe column with 10% NH₄OH in methanol (2×4 mL) and evaporated. Theresulting oil was purified as in 121JP34 to give 47 mg (54%) of 141JP13as a colourless oil. The L-tartrate salt was prepared as describedabove.

R_(f)=0.26 (MeOH/CH₂Cl₂ 1:10). LCMS m/z 508[M+H]⁺. ¹H-NMR (CDCl₃,rotamers 0.5:0.5) δ 8.47 and 8.41 (2s, 1H, —H), 7.48-6.89 (m, 8H, Ar—H),4.62-4.56 (m, 0.6H, pip-H), 4.56-4.49 (m, 3H, dioxane-H, benzyl-H),4.10-4.01 (m, 2H, dioxane-H), 3.79 and 3.61 (2s, 2H, benzyl-H),3.77-3.67 (m, 2.4H, pip-H, dioxane-H), 2.94-2.84 (m, 2H, pip-H),2.45-2.35 (m, 2H, NCH₂), 2.10-1.43 (m, 9H, dioxane-H, NCH₂CH₂, pip-H),1.37-1.27 (m, 1 H, dioxane-H).

In Vitro Determination of Receptor Activity

Receptor Selection and Amplification (R-SAT) Assays. The functionalreceptor assay, Receptor Selection and Amplification Technology(R-SAT™), was used (with minor modifications from the proceduredescribed previously (Brann, M. R. U.S. Pat. No. 5,707,798, 1998; Chem.Abstr. 1998, 128, 111548) to screen compounds for efficacy at the5-HT_(2A) receptor. Briefly, NIH3T3 cells were grown in 96 well tissueculture plates to 70-80% confluence. Cells were transfected for 12-16 hwith plasmid DNAs using superfect (Qiagen Inc.) as per manufacturer'sprotocols. R-SAT's were generally performed with 50 ng/well of receptorand 20 ng/well of β-galactosidase plasmid DNA. All receptor andG-protein constructs used were in the pSI mammalian expression vector(Promega Inc) as described previously. The 5-HT_(2A) receptor gene wasamplified by nested PCR from brain cDNA using the oligodeoxynucleotidesbased on the published sequence (Saltzman et. al, Biochem. Biophys. Res.Comm. 1991, 181, 1469). For large-scale transfections, cells weretransfected for 12-16 h, then trypsinized and frozen in DMSO. Frozencells were later thawed, plated at 10,000-40,000 cells per well of a 96well plate that contained drug. With both methods, cells were then grownin a humidified atmosphere with 5% ambient CO₂ for five days. Media wasthen removed from the plates and marker gene activity was measured bythe addition of the β-galactosidase substrate o-nitrophenylβ-D-galactopyranoside (ONPG, in PBS with 5% NP-40). The resultingcolorimetric reaction was measured in a spectrophotometric plate reader(Titertek Inc.) at 420 nM. All data were analyzed using the computerprogram XLFit (IDBSm). Efficacy is the percent maximal repressioncompared to repression by a control compound (ritanserin in the case of5-HT_(2A)). pIC₅₀ is the negative of the log(IC₅₀), where IC₅₀ is thecalculated concentration in Molar that produces 50% maximal repression.

In Vivo Determination of Behavioral Effects

Animals and Apparatus. Male NSA mice (Harlan; San Deigo, Calif.) wereused as subjects. Mice weighed 20-30 g. Animals were housed 8/cage inthe One Cage system (One Cage; Lab Products, Inc., Seaford, Del.) withbedding (⅛ inch Bed “O” Cob; Harlan Teklad, Madison, Wis.) in a roomwith controlled temperature 22±3° C. and a 12 hour light:dark cycle(lights on 6 am). Water and standard rodent chow (Harlan Teklad) werecontinuously available in the home cage. For testing, plastic locomotoractivity cages (20×20×30 cm; AccuScan Instruments, Columbus, Ohio) wereequipped with photocell beams for monitoring horizontal activity. Datawere collected using Versamax computer software (AccuScan Instruments).

Procedure.

For determination of spontaneous activity, test compounds wereadministered alone (s.c. 10 min or p.o. 30 min before the session). Forhyperactivity experiments, mice were injected with 0.3 mg/kg MK-801 i.p.15 min presession (the peak dose for producing hyperactivity in aninverted-U dose-effect curve as determined in pilot experiments) incombination with vehicle or test compound. Motor activity data werecollected during a 15 min session in a lit room. Mice had no priorexposure to the motor cages. Each dose or dose combination was tested ina separate group of mice (n=8).

Data Analysis.

Distance traveled (cm) was calculated and averaged across animals in agroup. An analysis of variance (ANOVA) and post-hoc Dunnett's t-testcomparions to vehicle control were conducted for each dose-responsefunction. The lowest dose found to be significantly different fromvehicle control was defined as the minimum effective dose (MED).

Compound Activity TABLE 1 MED 5HT2A %INH 5HT2A pIC50 in vivo po (mg/kg)103NLS45-B

84 7.6 117NLS01

104 9.7 1 103NLS63-F

101 9.5 103NLS69-A

96 8.7 117NLS03-B

85 8.4 117NLS25

94 8.9 128NLS22-A

98 8.5 118AF37-88

105 9.2 098AF76-65

100 9.1 118AF16-80

103 9.1

1. A compound of Formula I

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof,wherein R¹ is selected from the group consisting of optionallysubstituted heterocyclyl, and optionally substituted(heterocyclyl)C₁₋₆-alkyl; R² and R³ are independently selected from thegroup consisting of hydrogen, C₁₋₆-alkyl and halogen or such that R²together with R³ forms a ring; m is selected from the group consistingof 0, 1, and 2; n is selected from the group consisting of 1, 2, and 3;Ar¹ is an optionally substituted aryl or heteroaryl; W is selected fromthe group consisting of oxygen and sulfur; X is selected from the groupconsisting of optionally substituted methylene, optionally substitutedethylene, optionally substituted propylene, optionally substitutedvinylene, and CH₂N(R^(N)), wherein R^(N) is selected from hydrogen andC₁₋₆-alkyl; and Ar² is an optionally substituted aryl or heteroaryl. 2.The compound of claim 1, wherein said heterocyclyl or said(heterocycly)C₁₋₆-alkyl is optionally substituted with one or moregroups selected from the group consisting of hydrogen, halogen, hydroxy,alkoxy, alkyl, and amino.
 3. The compound of claim 1, wherein saidheterocyclyl is selected from the group conssiting oftetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane.
 4. The compound of claim 1, wherein R¹ is selected fromthe group consisting of an optionally substituted (heterocyclyl)methyl,an optionally substituted (heterocyclyl)ethyl, or an optionallysubstituted (heterocyclyl)propyl.
 5. The compound of claim 1, wherein R²and R³ are hydrogen, m is 1, n is 1, and W is oxygen.
 6. The compound ofclaim 1, wherein Ar¹ is an optionally substituted aryl, selected fromthe group consisting of alkyl-substituted phenyl, alkoxy-substitutedphenyl, halogen-substituted phenyl, hydroxy-substituted phenyl andamino-substituted phenyl, wherein said alkyl is selected from the groupconsisting of methyl, ethyl, propyl, n-butyl, sec-butyl and tert-butyl,and said alkoxy is selected from the group consisting of methoxy,ethoxy, propxy, n-butoxy, sec-butoxy, and tert-butoxy.
 7. The compoundof claim 1, wherein Ar¹ is 4-substituted aryl.
 8. The compound of claim7, wherein Ar¹ is halogen-substituted phenyl.
 9. The compound of claim1, wherein X is selected from the group consisting of optionallysubstituted methylene, optionally substituted ethylene, and CH₂N(R^(N)).10. The compound of claim 9, wherein X is CH₂N(R^(N)).
 11. The compoundof claim 1, wherein Ar² is an aryl optionally substituted with asubstituent selected from the group consisting of alkyl, alkoxy,halogen, hydroxy, amino, alkylamino, heteroaryl, and heterocyclyl. 12.The compound of claim 1, wherein Ar² is 4-substituted aryl.
 13. Thecompound of claim 11, wherein said substituent on Ar² is selected fromthe group consisting of chloro, fluoro, hydroxy, methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,trifluoromethoxy, N-morpholinyl, N-pyrrolidinyl, N-pyrazolyl,N-triazolyl and 2-oxopyrrolidinyl.
 14. The compound of claim 1, whereinsaid compound is selected from the group consisting of:N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isobutoxybenzyl)carbamide,hydrochloride;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-hydroxy-2-methylpropoxy)phenyl]acetamide,tartrate;N-{1-[3-(3,5-Dimethylpiperidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,dihydrochloride;1-[3-(4-{(4-Fluorobenzyl)-[2-(4-isobutoxyphenyl)acetyl]amino}piperidin-1-yl)propyl]piperidine-4-carboxylicacid methyl ester, dihydrochloride;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1-methylpyrrolidin-2-yl)ethyl]piperidin-4-yl}acetamide,dioxalate;N-{1-[3-(2,6-Dimethylmorpholin-4-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,dioxalate;N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxypiperidin-1-yl)propyl]piperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide,dioxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)N-{1-[3-(2-methylpiperidin-1-yl)propyl]piperidin-4-yl}acetamide,dioxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl}N-[1-(3-pyrrolidin-1-yl-propyl)piperidin-4-yl]acetamide,dioxalate;N-{1-[3-(2,5-Dimethylpyrrolidin-1-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,dioxalate;N-(4-Fluorobenzyl)-N-{1-[3-(3-hydroxymethylpiperidin-1-yl)propyl]piperidin-4-yl}-2-(4-isobutoxyphenyl)acetamide,dioxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate;N-[2-(4-Fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate;N-[2-(4-Fluorophenyl)ethyl]-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide,oxalate;N-(4-Fluorobenzyl)-N-{1-[3-(4-(S)-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}-2-(4-propoxyphenyl)acetamide,oxalate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-2-(4-isobutoxyphenyl)acetamide,oxalate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-[2-(4-fluorophenyl)ethyl]-2-(4-propoxyphenyl)acetamide,oxalate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isobutoxybenzyl)carbamide,tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-p-tolylacetamide,tartrate;2-Benzofuran-5-yl-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate;2-(2,3-Dihydrobenzofuran-5-yl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate;N-{1-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethylphenyl)acetamide,tartrate;2-(4-Cyanophenyl)-N-{1-[2-(1,3-dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide,hydrochloride;2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide,hydrochloride;N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[2-(2-oxo-imidazolidin-1-yl)ethyl]piperidin-4-yl}acetamide,hydrochloride;N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)propyl]piperidin-4-yl}acetamide;hydrochloride;N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-2-(4-methoxyphenyl)-N-(4-methylbenzyl)acetamide,hydrochloride;2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)propyl]piperidin-4-yl}-acetamide,hydrochloride;N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-{1-[4-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)butyl]piperidin-4-yl}acetamide,hydrochloride;N-{1-[2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)acetamide,hydrochloride;N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isopropoxy-benzyl)carbamide,oxalate;N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl]-2-(4-methoxyphenyl}N-(4-methylbenzyl)acetamide,hydrochloride;N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,hydrochloride;N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-isopropoxyphenyl)-N-(4-methylbenzyl)acetamide,hydrochloride;N-{1-[2-(1,3-Dioxolan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide,tartrate;N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolane-2-yl)ethyl]piperidin-4-yl}carbamide,oxalate;N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-[1-(3-morpholin-4-yl-propyl)piperidin-4-yl]carbamide,oxalate;2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-morpholin-4-ylethyl)piperidin-4-yl]acetamide,dihydrochloride;2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(3-morpholin-4-ylpropyl)piperidin-4-yl]acetamide,dihydrochloride;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(3-morpholin-4-ylpropyl)piperidin-4-yl]acetamide,dihydrochloride;N-(4-Fluorobenzyl)-2-(4-isopropoxyphenyl)-N-[1-(3-morpholin-4-yl-propyl)piperidin-4-yl]acetamide,dihydrochloride;N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-[1-(3-piperidin-1-yl-propyl)piperidin-4-yl]carbamide,oxalate;N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-[1-(3-((S)-4-isopropyl-2-oxazolidinon-1-yl-propyl)piperidin-4-yl]carbamide,tartrate;N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]}piperidin-4-yl]carbamide,oxalate;N-{1-[3-(1,3-Dioxolan-2-yl)propyl]piperidin-4-yl}-N-(4-fluorobenzyl)-N′-(4-isopropoxybenzyl)carbamide,oxalate;N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-N′-(4-isopropoxybenzyl)carbamide,oxalate; N-(4-Fluorobenzyl)-N′-(4-isopropoxybenzyl)-N-{[2-(1-methylpyrrolidin-2-yl)ethyl]-piperidin-4-yl}carbamide, oxalate;N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate;N-[1-(1,3-Dioxan-5-yl)-piperidin-4-yl)-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide,tartrate:N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxyphenyl)acetamide,tartrate:N-{1-[2-(1,3-Dioxan-4-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propoxyphenyl)acetamide,tartrate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]acetamide,tartrate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(tetrahydropyran-4-ylmethyl)piperidin-4-yl]acetamide,tartrate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-4-yl)ethyl]piperidin-4-yl]acetamide,tartrate;N-(4-Fluorobenzyl)-2-(4-fluorophenyl)-N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]acetamide,tartrate;N-[1-((S)-3,5-Dihydroxypentyl)piperidine-4-yl]-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;N-{1-[2-((4S)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate;2-(4-Benzyloxyphenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-hydroxyphenylacetamide,tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-methoxyphenyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropylphenyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-trifluoromethoxy-phenyl)acetamide,tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-ethoxyphenyl)-acetamide,oxalate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isopropoxyphenyl)-acetamide,oxalate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-phenylacetamide,oxalate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-fluoroethoxy)-phenyl]acetamide,oxalate;N-{1-[2-(5,5-Dimethyl-1,3dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}acetamide,oxalate;N-{1-[2-(4,6-Dimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,oxalate;N-(4-Fluorobenzyl)-N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide,oxalate;N-(4-Fluorobenzyl)-2-(4-isopropylphenyl}N-{1-[2-((S)-4-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate; N-(4-Fluorobenzyl)-N-{1-[2-((R)-4-methyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-2-(4-trifluoromethoxyphenyl)acetamide, oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]piperidin-4-yl}acetamide, oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-piperidin-4-yl}acetamide,oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(1,3-dioxolan-2-yl)propyl]piperidin-4-yl}acetamide,tartrate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-(3-piperidin-1-yl-propyl)piperidin-4-yl}-acetamide,dihydrochloride;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(tetrahydropyran-2-yloxy)ethyl]-piperidin-4-yl}acetamide,oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-piperidin-1-yl)propyl]piperidin-4-yl}acetamide;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-pyrrolidin-1-yl)propyl]piperidin-4-yl}acetamide,hydrochloride;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-(2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-methyl-2-oxo-oxazolidin-3-yl)propyl]piperidin-4-yl}acetamide,tartrate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[3-((S)-4-ethyl-2-oxo-oxazolidin-3-yl)-propyl]piperidin-4-yl}acetamide,oxalate;N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-{1-[2-(1,3-oxothiolan-2-yl)ethyl]piperidin-4-yl}acetamide,L-tartrate;2-(4-Bromophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutylamino-phenyl)acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-propylamino-phenyl)acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-(1-nitropropyl)-phenyl)acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(2-oxopyrrolidin-1-yl)phenyl)acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutylsulfanyl-phenyl)acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-iodophenyl)-acetamide,L-tartrate;2-(4-Acetophenyl)-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-acetamide,L-tartrate;2-[4-(1-Hydroxyiminoethyl)phenyl]-N-{1-[2-(1,3-dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-morpholin-4-yl-phenyl)acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyrazol-1-ylphenyl)acetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-2-yl)-1-methylethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenylacetamide,L-tartrate;N-{1-[2-(1,3-Dioxan-4-yl)ethyl)piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-pyrazol-1-ylphenyl)acetamide,L-tartrate;N-{1-[2-((4R)-1,3-Dioxane-4-yl)ethyl]piperidine-4-yl}-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide,tartrate; andN-{1-[2-(1,3-Dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-[4-(1,2,4-triazol-4-yl)phenyl]acetamide,L-tartrate.
 15. A pharmaceutical composition comprising at least onecompound of claim 1 and a pharmaceutically acceptable carrier, eluent,or excipient.
 16. A method of inhibiting an activity of a monoaminereceptor comprising contacting the monoamine receptor or a systemcontaining the monoamine receptor with an amount of one or more of thecompounds of claim 1 that is effective in inhibiting the activity of themonoamine receptor.
 17. The method of claim 16, wherein the monoaminereceptor is a serotonin receptor.
 18. The method of claim 17, whereinthe serotonin receptor is the 5-HT2A subclass.
 19. The method of claim17, wherein the serotonin receptor is in the central nervous system. 20.The method of claim 17, wherein the serotonin receptor is in theperipheral nervous system.
 21. The method of claim 17, wherein theserotonin receptor is in blood cells or platelets.
 22. The method ofclaim 17, wherein the serotonin receptor is mutated or modified.
 23. Themethod of claim 16, wherein the activity is signaling activity.
 24. Themethod of claim 16, wherein the activity is constitutive.
 25. The methodof claim 16, wherein the activity is associated with serotonin receptoractivation.
 26. A method of inhibiting an activation of a monoaminereceptor comprising contacting the monoamine receptor or a systemcontaining the monoamine receptor with an amount of a compound of one ormore of the compounds of claim 1 that is effective in inhibiting theactivation of the monoamine receptor.
 27. The method of claim 26,wherein the activation is by an agonistic agent.
 28. The method of claim27, wherein the agonistic agent is exogenous.
 29. The method of claim27, wherein the agonistic agent is endogenous.
 30. The method of claim26, wherein the activation is constitutive.
 31. The method of claim 26,wherein the monoamine receptor is a serotonin receptor.
 32. The methodof claim 31, wherein the serotonin receptor is the 5-HT2A subclass. 33.The method of claim 31, wherein the serotonin receptor is in the centralnervous system.
 34. The method of claim 31, wherein the serotoninreceptor is in the peripheral nervous system.
 35. The method of claim31, wherein the serotonin receptor is in blood cells or platelets. 36.The method of claim 31, wherein the serotonin receptor is mutated ormodified.
 37. A method of alleviating at least one symptom of a diseasecondition associated with a monoamine receptor comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of one or more of the compounds of claim
 1. 38. The method ofclaim 37, wherein the disease condition is selected from the groupconsisting of schizophrenia, schizoaffective disorders, psychosis, druginduced psychosis, and side effects observed with the treatment ofchronic neurodegenerative disorders with a selective serotonin reuptakeinhibitor (SSRI).
 39. The method of claim 38, wherein saidneurodegenerative disorder is selected from Alzheimer's disease,Parkinson's disease, Lewy Body Dementia, Frontotemporal Dementia,Spinocerebellar Atrophy, and Huntington's disease.
 40. The method ofclaim 37, wherein the disease condition is selected from the groupconsisting of Reynaud's Phenomena, migraine, hypertension, thrombosis,vasospasm, ischemia, depression, anxiety, motor tics, Tourette'ssyndrome, dyskinesias, on/off phenomena, tremor, rigidity, bradykinesia,psychomotor slowing, addiction, including alcohol addiction, opioidaddiction, and nicotine addiction, sleep disorders, appetite disorders,and decreases in libido and ejaculatory problems.
 41. The method ofclaim 37, wherein the disease condition is associated with dysfunctionof a monoamine receptor.
 42. The method of claim 37, wherein the diseasecondition is associated with activation of a monoamine receptor.
 43. Themethod of claim 37, wherein the disease condition is associated withincreased activity of monoamine receptor.
 44. The method of claim 37,wherein the monoamine receptor is a serotonin receptor
 45. The method ofclaim 44, wherein the serotonin receptor is the 5-HT2A subclass.
 46. Themethod of claim 44, wherein the serotonin receptor is in the centralnervous system.
 47. The method of claim 44, wherein the serotoninreceptor is in the peripheral nervous system.
 48. The method of claim44, wherein the serotonin receptor is in blood cells or platelets. 49.The method of claim 44 wherein the serotonin receptor is mutated ormodified.
 50. A method of treating schizophrenia comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of one or more of the compounds ofclaim
 1. 51. A method of treating migraine comprising administering to asubject in need of such treatment a therapeutically effective amount ofa compound of one or more of the compounds of claim
 1. 52. A method oftreating psychosis comprising administering to a subject in need of suchtreatment a therapeutically effective amount of a compound of one ormore of the compounds of claim
 1. 53. A method for identifying a geneticpolymorphism predisposing a subject to being responsive to one or moreof the compounds of claim 1, comprising: administering to a subject atherapeutically effective amount of the compound; measuring the responseof said subject to said compound, thereby identifying a responsivesubject having an ameliorated disease condition associated with amonoamine receptor; and identifying a genetic polymorphism in theresponsive subject, wherein the genetic polymorphism predisposes asubject to being responsive to the compound.
 54. The method of claim 53wherein the ameliorated disease condition is associated with the 5-HTclass or 5-HT2A subclass of monoaminergic receptors.
 55. A method foridentifying a subject suitable for treatment with one or more of thecompounds of claim 1, comprising detecting the presence of apolymorphism in a subject wherein the polymorphism predisposes thesubject to being responsive to the compound, and wherein the presence ofthe polymorphism indicates that the subject is suitable for treatmentwith one or more of the compounds of claim
 1. 56. A method ofalleviating a condition associated with non-selective antipsychoticcompounds comprising administering a therapeutically effective amount ofone or more of the compounds of claim 1 to a subject suffering from saidcondition.
 57. The method according to claim 56, wherein the compound ofclaim 1 is a selective antagonist or inverse agonist of a 5-HT2Areceptor.
 58. The method of according to claim 56, wherein the compoundof claim 1 has little to no activity on other monamine receptors. 59.The method according to claim 58, wherein one of the other monaminereceptors is a dopamine D2 receptor.
 60. A method of alleviating acondition which is a side effect which can arise in an individual whotakes an antipsychotic compound which possess broad activity at multiplemonamine receptors subtypes, comprising administering a therapeuticallyeffective amount of one or more of the compounds of claim 1 to subjectsuffering from said condition.
 61. The method according to claim 60,wherein the compound of claim 1 is a selective antagonist or inverseagonist of a 5-HT2A receptor.
 62. The method of according to claim 60,wherein the compound of claim 1 has little to no activity on othermonamine receptors.
 63. The method according to claim 62, wherein one ofthe other monamine receptors is a dopamine D2 receptor.